Author: "Amélie Trinquand" - Searchworks@Jio Institute Digital Library Search Results

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1. P327: LOSS OF POLYCOMB REPRESSIVE COMPLEX 2 FUNCTION CAUSES ASPARAGINASE RESISTANCE IN T-ACUTE LYMPHOBLASTIC LEUKAEMIA THROUGH DECREASED WNT PATHWAY ACTIVITY

Author: Thomas Lefeivre, Cosmin Tudose, Theodora Grosu, Luke Jones, Theresa Leon, Kieran Wynne, Giorgio Oliviero, Owen Smith, Amélie Trinquand, Marc Mansour, Colm Ryan, and Jonathan Bond
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Published: 2023
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2. Toward Pediatric T Lymphoblastic Lymphoma Stratification Based on Minimal Disseminated Disease and NOTCH1/FBXW7 Status

Author: Amélie Trinquand, Adriana Plesa, Chrystelle Abdo, Fabien Subtil, Nathalie Aladjidi, Charlotte Rigaud, Aurore Touzart, Ludovic Lhermitte, Arnaud Petit, Katell Michaux, Charlotte Jung, Catherine Chassagne-Clement, Vahid Asnafi, Yves Bertrand, Nathalie Garnier, and Elizabeth Macintyre
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: While outcome for pediatric T lymphoblastic lymphoma (T-LL) has improved with acute leukemia-type therapy, survival after relapse remains rare. Few prognostic markers have been identified: NOTCH1 and/or FBXW7 (N/F) mutations identify good prognosis T-LL and high-level minimal disseminated disease (MDD) is reported to be of poor prognosis. We evaluated MDD and/or MRD status by 8-color flow cytometry and/or digital droplet PCR in 82 pediatric T-LL treated according to the EURO-LB02 prednisone reference arm. Both techniques gave identical results for values ≥0.1%, allowing compilation. Unlike historical studies, an MDD threshold of 1% had no prognostic significance. The 54% (42/78) of patients with MDD ≥0.1% had a relatively favorable outcome (5-y overall survival [OS] 97.6% versus 80.6%, P = 0.015, 5-y event-free-survival [EFS] 95.2% versus 80.6%, P = 0.049). MDD lower than 0.1% had no impact in N/F mutated T-LL, but identified the N/F germline patient with a high risk of relapse. Combining oncogenetic and MDD status identified 86% of patients (n = 49) with an excellent outcome and 14% of N/F germline/MDD
Published: 2021
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3. Safety and efficacy of brentuximab vedotin as a treatment for lymphoproliferative disorders in primary immunodeficiencies

Author: Thomas Pincez, Julie Bruneau, Laureline Berteloot, Eve Piekarski, Caroline Thomas, Ambroise Marçais, Amélie Trinquand, Martin Castelle, Nicolas Garcelon, Dominique Plantaz, Morgane Cheminant, Despina Moshous, Thierry Jo Molina, Olivier Hermine, Elizabeth Macintyre, Alain Fischer, Stéphane Blanche, Felipe Suarez, and Bénédicte Neven
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Published: 2020
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4. Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress

Author: Tim I. M. Malcolm, Patrick Villarese, Camilla J. Fairbairn, Laurence Lamant, Amélie Trinquand, C. Elizabeth Hook, G. A. Amos Burke, Laurence Brugières, Katherine Hughes, Dominique Payet, Olaf Merkel, Ana-Iris Schiefer, Ibraheem Ashankyty, Shahid Mian, Mariusz Wasik, Martin Turner, Lukas Kenner, Vahid Asnafi, Elizabeth Macintyre, and Suzanne D. Turner
Subjects: Science
Abstract: Anaplastic large cell lymphoma is characterized by an NPM–ALK fusion but the cell of origin for this cancer is unclear. Here, the authors show that, in an NPM–ALK mouse model, the tumours likely arise from early thmyocytes and require an initial burst of TCR signalling for initiation.
Published: 2016
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5. An early thymic precursor phenotype predicts outcome exclusively in HOXA-overexpressing adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study

Author: Jonathan Bond, Tony Marchand, Aurore Touzart, Agata Cieslak, Amélie Trinquand, Laurent Sutton, Isabelle Radford-Weiss, Ludovic Lhermitte, Salvatore Spicuglia, Hervé Dombret, Elizabeth Macintyre, Norbert Ifrah, Jean-François Hamel, and Vahid Asnafi
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Gene expression studies have consistently identified a HOXA-overexpressing cluster of T-cell acute lymphoblastic leukemias, but it is unclear whether these constitute a homogeneous clinical entity, and the biological consequences of HOXA overexpression have not been systematically examined. We characterized the biology and outcome of 55 HOXA-positive cases among 209 patients with adult T-cell acute lymphoblastic leukemia uniformly treated during the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003 and -2005 studies. HOXA-positive patients had markedly higher rates of an early thymic precursor-like immunophenotype (40.8% versus 14.5%, P=0.0004), chemoresistance (59.3% versus 40.8%, P=0.026) and positivity for minimal residual disease (48.5% versus 23.5%, P=0.01) than the HOXA-negative group. These differences were due to particularly high frequencies of chemoresistant early thymic precursor-like acute lymphoblastic leukemia in HOXA-positive cases harboring fusion oncoproteins that transactivate HOXA. Strikingly, the presence of an early thymic precursor-like immunophenotype was associated with marked outcome differences within the HOXA-positive group (5-year overall survival 31.2% in HOXA-positive early thymic precursor versus 66.7% in HOXA-positive non-early thymic precursor, P=0.03), but not in HOXA-negative cases (5-year overall survival 74.2% in HOXA-negative early thymic precursor versus 57.2% in HOXA-negative non-early thymic precursor, P=0.44). Multivariate analysis further revealed that HOXA positivity independently affected event-free survival (P=0.053) and relapse risk (P=0.039) of chemoresistant T-cell acute lymphoblastic leukemia. These results show that the underlying mechanism of HOXA deregulation dictates the clinico-biological phenotype, and that the negative prognosis of early thymic precursor acute lymphoblastic leukemia is exclusive to HOXA-positive patients, suggesting that early treatment intensification is currently suboptimal for therapeutic rescue of HOXA-positive chemoresistant adult early thymic precursor acute lymphoblastic leukemia. Trial Registration: The GRAALL-2003 and -2005 studies were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.
Published: 2016
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6. Minimal residual disease monitoring by 8-color flow cytometry in mantle cell lymphoma: an EU-MCL and LYSA study

Author: Morgane Cheminant, Coralie Derrieux, Aurore Touzart, Stéphanie Schmit, Adrien Grenier, Amélie Trinquand, Marie-Hélène Delfau-Larue, Ludovic Lhermitte, Catherine Thieblemont, Vincent Ribrag, Stéphane Cheze, Laurence Sanhes, Fabrice Jardin, François Lefrère, Richard Delarue, Eva Hoster, Martin Dreyling, Vahid Asnafi, Olivier Hermine, and Elizabeth Macintyre
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Quantification of minimal residual disease may guide therapeutic strategies in mantle cell lymphoma. While multiparameter flow cytometry is used for diagnosis, the gold standard method for minimal residual disease analysis is real-time quantitative polymerase chain reaction (RQ-PCR). In this European Mantle Cell Lymphoma network (EU-MCL) pilot study, we compared flow cytometry with RQ-PCR for minimal residual disease detection. Of 113 patients with at least one minimal residual disease sample, RQ-PCR was applicable in 97 (86%). A total of 284 minimal residual disease samples from 61 patients were analyzed in parallel by flow cytometry and RQ-PCR. A single, 8-color, 10-antibody flow cytometry tube allowed specific minimal residual disease assessment in all patients, with a robust sensitivity of 0.01%. Using this cut-off level, the true-positive-rate of flow cytometry with respect to RQ-PCR was 80%, whereas the true-negative-rate was 92%. As expected, RQ-PCR frequently detected positivity below this 0.01% threshold, which is insufficiently sensitive for prognostic evaluation and would ideally be replaced with robust quantification down to a 0.001% (10-5) threshold. In 10 relapsing patients, the transition from negative to positive by RQ-PCR (median 22.5 months before relapse) nearly always preceded transition by flow cytometry (4.5 months), but transition to RQ-PCR positivity above 0.01% (5 months) was simultaneous. Pre-emptive rituximab treatment of 2 patients at minimal residual disease relapse allowed re-establishment of molecular and phenotypic complete remission. Flow cytometry minimal residual disease is a complementary approach to RQ-PCR and a promising tool in individual mantle cell lymphoma therapeutic management.
Published: 2016
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7. Supplementary Methods, Figure Legends, Table Legend from Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia

Author: Vahid Asnafi, Jacques Ghysdael, Elizabeth Macintyre, Olivier Hermine, David-Alexandre Gross, Lucienne Chatenoud, Salvatore Spicuglia, Hervé Dombret, Norbert Ifrah, Françoise Pflumio, Els Verhoeyen, François-Loïc Cosset, Michael Dussiot, Melania Tesio, Ludovic Lhermitte, Cindy Da Costa de Jesus, Mohamed Belhocine, Benedetta Zaniboni, Francesca Rocchetti, Christine Tran Quang, Nuno R. dos Santos, and Amélie Trinquand
Abstract: Supplementary Methods, Figure Legends, Table Legend
Published: 2023

8. Supplementary Figures 1 - 3, Table 1 from Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia

Author: Vahid Asnafi, Jacques Ghysdael, Elizabeth Macintyre, Olivier Hermine, David-Alexandre Gross, Lucienne Chatenoud, Salvatore Spicuglia, Hervé Dombret, Norbert Ifrah, Françoise Pflumio, Els Verhoeyen, François-Loïc Cosset, Michael Dussiot, Melania Tesio, Ludovic Lhermitte, Cindy Da Costa de Jesus, Mohamed Belhocine, Benedetta Zaniboni, Francesca Rocchetti, Christine Tran Quang, Nuno R. dos Santos, and Amélie Trinquand
Abstract: Supplementary Figure 1. Anti-CD3 stimulation of primary human T-ALLs. Supplementary Figure 2. TCR stimulation by in vivo administration of agonistic monoclonal antibody in a preventive setting inhibits human TCR+ T-ALL development. Supplementary Figure 3. TCR signaling is essential to the anti-leukemic effect of OKT3. Supplementary Table 1. Immunophenotypic and oncogenic characteristics of T-ALL samples.
Published: 2023

9. Immature acute leukaemias: lessons from the haematopoietic roadmap

Author: Elisa Laurenti, Jonathan Bond, Antoine Pinton, Elizabeth Macintyre, Luke Jones, Amélie Trinquand, and Thomas Lefeivre
Subjects: 0301 basic medicine, Myeloid, Bioinformatics, Biochemistry, Blood cancer, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, medicine, Humans, Molecular Biology, Mixed phenotype acute leukaemia, business.industry, Cell Biology, Acute leukaemias, State of the art review, Hematopoiesis, 3. Good health, Leukemia, Myeloid, Acute, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Acute Disease, Normal blood, business
Abstract: It is essential to relate the biology of acute leukaemia to normal blood cell development. In this review, we discuss how modern models of haematopoiesis might inform approaches to diagnosis and management of immature leukaemias, with a specific focus on T-lymphoid and myeloid cases. In particular, we consider whether next-generation analytical tools could provide new perspectives that could improve our understanding of immature blood cancer biology.
Published: 2021

10. Safety and efficacy of AMG 714 in patients with type 2 refractory coeliac disease: a phase 2a, randomised, double-blind, placebo-controlled, parallel-group study

Author: Ciaran P. Kelly, Garbiñe Roy Ariño, Anthony J. DiMarino, George Vlad, Laura Crespo, Raquel Perez Maseda, Amélie Trinquand, Ralph Raymond, Michael Schumann, Anne Blanchard, Olivier Hermine, Georgia Malamut, Jane R. Parnes, Samuli Rounioja, Eric Butz, Valerie Byrnes, Hetty J. Bontkes, Wayne Tsuji, Christophe Cellier, Gerd Bouma, Beth Llewellyn, Nadine Cerf-Bensussan, Tom van Gils, Peter H.R. Green, Joseph A. Murray, Govind Bhagat, Jack D. Bui, Ashleigh Palmer, Bana Jabri, Knut E.A. Lundin, Elizabeth Macintyre, Pekka Collin, Carlota García-Hoz, Sherine Khater, Bertrand Meresse, Francisco Leon, Chris J. J. Mulder, Sheila E. Crowe, David S Sanders, Michel Azizi, Marios Hadjivassiliou, Keijo Viiri, Vrije Universiteit Medical Centre (VUMC), Vrije Universiteit Amsterdam [Amsterdam] (VU), Columbia University Medical Center (CUMC), Columbia University [New York], Department of Medicine, University of Washington [Seattle], Laboratory of Intestinal Immunity (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), CCSD, Accord Elsevier, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hospital Universitario Ramón y Cajal [Madrid], Universidad de Alcalá - University of Alcalá (UAH), Tampere University Hospital, University of California [San Diego] (UC San Diego), University of California (UC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Amgen Inc., RCD-II Study Group Investigators: Bana Jabri, Joseph Murray, Anthony DiMarino, Ciaran P Kelly, Valerie Byrnes, David Sanders, Knut Ea Lundin, Michael Schumann, Hetty Bontkes, Bertrand Meresse, Garbiñe Roy Ariño, Govind Bhagat, Keijo Viiri, Samuli Rounioja, Jack Bui, Raquel Perez Maseda, Carlota García-Hoz, Amelie Trinquand, George Vlad, Marios Hadjivassiliou, Michel Azizi, Anne Blanchard, Beth Llewellyn, Ashleigh Palmer, Ralph Raymond, Gastroenterology and hepatology, AGEM - Digestive immunity, AGEM - Re-generation and cancer of the digestive system, and AII - Inflammatory diseases
Subjects: medicine.medical_specialty, [SDV]Life Sciences [q-bio], Population, Placebo, Gastroenterology, Coeliac disease, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Biopsy, medicine, Clinical endpoint, Adverse effect, education, education.field_of_study, Hepatology, medicine.diagnostic_test, business.industry, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Intraepithelial lymphocyte, 030211 gastroenterology & hepatology, business
Abstract: Summary Background Refractory coeliac disease type 2 is a rare subtype of coeliac disease with high mortality rates; interleukin 15 (IL-15) is strongly implicated in its pathophysiology. This trial aimed to investigate the effects of AMG 714, an anti-IL-15 monoclonal antibody, on the activity and symptoms of refractory coeliac disease type 2. Methods This was a randomised, double-blind, placebo-controlled, phase 2a study of adults with a confirmed diagnosis of refractory coeliac disease type 2. Patients were randomly assigned at a 2:1 ratio to receive seven intravenous doses over 10 weeks of AMG 714 (8 mg/kg) or matching placebo. Biopsy samples were obtained at baseline and week 12 for cellular analysis and histology. The change in the proportion of aberrant intraepithelial lymphocytes from baseline to week 12 with respect to all intraepithelial lymphocytes was the primary endpoint and was quantified using flow cytometry. Secondary endpoints were the change in aberrant intraepithelial lymphocytes with respect to intestinal epithelial cells; intestinal histological scores (villous height-to-crypt depth ratio; VHCD); intraepithelial lymphocyte counts; Marsh score; and patient-reported symptom measures, including the Bristol stool form scale (BSFS) and gastrointestinal symptom rating scale (GSRS). Main analyses were done in the per-protocol population of patients who received their assigned treatment, provided evaluable biopsy samples, and did not have major protocol deviations; only patients with non-atypical disease were included in the analyses of aberrant intraepithelial lymphocytes, including the primary analysis. Safety was assessed in all patients who received at least one dose of study drug. This study is registered at ClinicalTrials.gov (NCT02633020) and EudraCT (2015-004063-36). Findings From April 13, 2016, to Jan 19, 2017, 28 patients were enrolled and randomly assigned to AMG 714 (n=19) and placebo (n=9). Six patients were not included in the primary analysis because of protocol deviation (one in the AMG 714 group), insufficient biopsy samples (one in the AMG 714 group), and atypical intraepithelial lymphocytes (three in the AMG 714 group and one in the placebo group). At 12 weeks, the least square mean difference between AMG 714 and placebo in the relative change from baseline in aberrant intraepithelial lymphocyte percentage was −4·85% (90% CI −30·26 to 20·56; p=0·75). The difference between the AMG 714 and placebo groups in aberrant intraepithelial lymphocytes with respect to epithelial cells at 12 weeks was −38·22% (90% CI −95·73 to 19·29; nominal p=0·18); the difference in change in Marsh score from baseline was 0·09% (95% CI −1·60–1·90; nominal p=0·92); the difference in VHCD ratio was 10·67% (95% CI −38·97 to 60·31; nominal p=0·66); and the difference in change in total intraepithelial lymphocyte count was −12·73% (95% CI −77·57–52·12); nominal p=0·69). Regarding symptoms, the proportion of patients with diarrhoea per the BSFS score decreased from ten (53%) of 19 at baseline to seven (37%) of 19 at week 12 in the AMG 714 group and increased from two (22%) of nine at baseline to four (44%) of nine at week 12 in the placebo group (nominal p=0·0008); and the difference between the groups in change in GSRS score was −0·14 (SE 0·19; nominal p=0·48). Eight (89%) patients in the placebo group and 17 (89%) in the AMG 714 group had treatment-emergent adverse events, including one (11%) patient in the placebo group and five (26%) in the AMG 714 group who had serious adverse events. The most common adverse event in the AMG 714 group was nasopharyngitis (eight [42%] patients vs one [11%] in the placebo group). Interpretation In patients with refractory coeliac disease type 2 who were treated with AMG 714 or placebo for 10 weeks, there was no difference between the groups in terms of the primary endpoint of aberrant intraepithelial lymphocyte reduction from baseline. Effects on symptoms and other endpoints suggest that further research of AMG 714 may be warranted in patients with refractory coeliac disease type 2. Funding Celimmune and Amgen.
Published: 2019

11. Long-Term Follow-up Study after Lentiviral Hematopoietic Stem/Progenitor Cell Gene Therapy for Wiskott - Aldrich Syndrome

Author: Salima Hacein-Bey-Abina, Adeline Denis, Alexandre Kauskot, Elizabeth Macintyre, Jin Hua Xu-Bayford, Aurélie Gabrion, Guy Gorochov, Cécile Roudaut, Chantal Lagresle-Peyrou, Aoife M. Doto, Capucine Picard, Frédéric Adam, Felipe Suarez, Alessandra Magnani, Frederic D. Bushman, Alain Fischer, Rachel Petermann, Emma C. Morris, Sarah Abbas, Emmanuel Clave, Marianne Guisset, Chrystelle Abdo, Christine Rivat, Loïc Dupré, Amélie Trinquand, Reem Elfeky, Marina Cavazzana, Elisa Magrin, Despina Moshous, Claire Booth, Anne Galy, Emmanuelle Six, Antoine Toubert, Bobby Gaspar, Adrian J. Thrasher, Mélanie Guiot, Delphine Borgel, Michaela Semeraro, John K. Everett, Makoto Miyara, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM), Great Ormond Street Hospital for Children [London] (GOSH), Great Ormond Street Institute of Child Health (UCL), University College of London [London] (UCL), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupement Hospitalier Universitaire Ouest, Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Hopital Saint-Louis [AP-HP] (AP-HP), Arthrites autoimmunes (AA), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'Immunologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Transfusion Sanguine [Paris] (INTS), Service d'immuno-hématologie pédiatrique [CHU Necker], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: business.industry, Wiskott–Aldrich syndrome, Long term follow up, Genetic enhancement, Immunology, Cell Biology, Hematology, medicine.disease, Biochemistry, Haematopoiesis, Cancer research, Medicine, Progenitor cell, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Wiskott Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency associated with thrombocytopenia, eczema, infectious, autoimmune complications, and lymphomas. Patients lacking an HLA-matched donor may benefit from an alternative therapeutic approach based on the infusion of autologous gene corrected CD34+ cells. We previously reported a non-randomised, open-label, phase 1/2 clinical study applying a lentiviral vector based gene therapy (GT) protocol in 7 paediatric patients with severe WAS (score ≥ 3/5) (S. Hacein-Bey Abina et al, JAMA 2015). One patient died 7 months after GT because of pre-existing severe opportunistic infections, as reported. Two additional patients have been treated since that initial report, with a follow-up of at least 4 years. We here present a comprehensive long-term study on 8 patients with a follow-up from 4 to 9 years (median 7.6). The safety and efficacy of the approach is thoroughly investigated, with a particular focus on the correction of thrombocytopenia and auto-immunity. A stable engraftment of genetically and functionally corrected lymphoid and myeloid cells was reached in all patients, with no serious treatment-associated adverse events or concerning clonal expansion. Corrected lymphoid cells displayed a selective advantage over time with increasing vector copy number (VCN) level. In turn, this led to (i) sustained expression of WAS protein (WASp) in the patients' cells and (ii) clinical resolution of severe eczema and susceptibility to recurrent infections. In line with these results, T-cell function was restored after GT, as shown by the recovery of immune synapse assembly and the normalization of naïve T cell numbers. The T-cell compartment was also reconstituted in the patient treated at the age of 30 years, suggesting that GT for WAS is a treatment option in adult patients. In parallel with the robustness of T-cell reconstitution a normalized B-cell compartment was observed after GT, as shown in particular by increasing levels of WASp + switched memory B cells over time and the age-matched levels of KRECs. Five patients out of 8 were able to discontinue Ig replacement therapy while achieving normal post-vaccination antibody titers. Autoimmune disorders and bleeding episodes were significantly less frequent, despite only partial correction of the platelet compartment. After GT, a few autoimmune manifestations were observed: the persistence of lower extremity vasculitis (P2, very severe prior to GT), the new occurrence of nephrotic syndrome (P9), and the presence of anti-platelet antibodies (P2, P4, P7). The levels of circulating autoantibodies detected before GT (including ANA and vasculitis-related autoantibodies) normalized after treatment. Following GT, platelets were found to express sub-normal levels of WASp and to only partially augment their size. Platelet function studies indicated a partial correction of the platelet compartment achieved by GT, which may be sufficient to prevent occurrence of the hemorrhagic symptoms typical of WAS. Our results suggest that lentiviral GT provides sustained clinical benefits for patients with WAS. Overall clinical remission was observed in our patients despite very severe disease scores before GT. More efficacious and more reliable transduction protocols and conditioning regimen are likely to further improve outcomes, particularly with regard to platelet recovery, where the advantages of intrinsic correction are less apparent. Disclosures Booth: Orchard Therapeutics: Consultancy, Honoraria; SOBI: Consultancy, Honoraria; Takeda: Honoraria; GSK: Honoraria; Rocket Pharmaceuticals, Inc.: Consultancy. Thrasher: Orchard Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; 4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cavazzana: Smart Immune: Other: co-founder.
Published: 2021

12. Toward Pediatric T Lymphoblastic Lymphoma Stratification Based on Minimal Disseminated Disease and NOTCH1/FBXW7 Status

Author: Nathalie Aladjidi, Amélie Trinquand, Catherine Chassagne-Clément, Arnaud Petit, Elizabeth Macintyre, Yves Bertrand, Charlotte Jung, Fabien Subtil, Katell Michaux, Chrystelle Abdo, Vahid Asnafi, Nathalie Garnier, Ludovic Lhermitte, Aurore Touzart, Adriana Plesa, Charlotte Rigaud, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Lyon, CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hospices Civils de Lyon (HCL), Centre Léon Bérard [Lyon], Gestionnaire, HAL Sorbonne Université 5, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.medical_specialty, Poor prognosis, Gastroenterology, Article, 03 medical and health sciences, 0302 clinical medicine, Prednisone, Internal medicine, medicine, Mutational status, Diseases of the blood and blood-forming organs, Favorable outcome, Prospective cohort study, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, 3. Good health, 030220 oncology & carcinogenesis, Minimal Disseminated Disease, Good prognosis, RC633-647.5, business, T-Lymphoblastic Lymphoma, 030215 immunology, medicine.drug
Abstract: International audience; While outcome for pediatric T lymphoblastic lymphoma (T-LL) has improved with acute leukemia-type therapy, survival after relapse remains rare. Few prognostic markers have been identified: NOTCH1 and/or FBXW7 (N/F) mutations identify good prognosis T-LL and high-level minimal disseminated disease (MDD) is reported to be of poor prognosis. We evaluated MDD and/or MRD status by 8-color flow cytometry and/or digital droplet PCR in 82 pediatric T-LL treated according to the EURO-LB02 prednisone reference arm. Both techniques gave identical results for values ≥0.1%, allowing compilation. Unlike historical studies, an MDD threshold of 1% had no prognostic significance. The 54% (42/78) of patients with MDD ≥0.1% had a relatively favorable outcome (5-y overall survival [OS] 97.6% versus 80.6%, P = 0.015, 5-y event-free-survival [EFS] 95.2% versus 80.6%, P = 0.049). MDD lower than 0.1% had no impact in N/F mutated T-LL, but identified the N/F germline patient with a high risk of relapse. Combining oncogenetic and MDD status identified 86% of patients (n = 49) with an excellent outcome and 14% of N/F germline/MDD
Published: 2021

13. Safety and efficacy of brentuximab vedotin as a treatment for lymphoproliferative disorders in primary immunodeficiencies

Author: Morgane Cheminant, Felipe Suarez, Thomas Pincez, Elizabeth Macintyre, Laureline Berteloot, Julie Bruneau, Dominique Plantaz, Stéphane Blanche, Martin Castelle, Olivier Hermine, Ambroise Marçais, Bénédicte Neven, Alain Fischer, Eve Piekarski, Thierry Jo Molina, Nicolas Garcelon, Amélie Trinquand, Caroline Thomas, and Despina Moshous
Subjects: Oncology, Brentuximab Vedotin, medicine.medical_specialty, Immunoconjugates, business.industry, Hematopoietic stem cell, Lymphoproliferative disorders, Ki-1 Antigen, Hematology, medicine.disease, Lymphoproliferative Disorders, medicine.anatomical_structure, Treatment Outcome, Internal medicine, medicine, Humans, Brentuximab vedotin, business, Letters to the Editor, medicine.drug
Published: 2020

14. Towards molecular stratification of pediatric T-cell lymphoblastic lymphomas based on Minimal Disseminated Disease andNOTCH1/FBXW7mutational status: the French EURO-LB02 experience

Author: Arnaud Petit, Catherine Chassagne-Clément, Elizabeth Macintyre, Chrystelle Abdo, Yves Bertrand, Charlotte Jung, Charlotte Rigaud, Katell Michaux, Aurore Touzart, Vahid Asnafi, Nathalie Garnier, Nathalie Aladjidi, Ludovic Lhermitte, Amélie Trinquand, and Adriana Plesa
Subjects: Oncology, medicine.medical_specialty, Poor prognosis, business.industry, T cell, Minimal residual disease, medicine.anatomical_structure, Internal medicine, medicine, Minimal Disseminated Disease, Mutational status, Good prognosis, Favorable outcome, business, T-Lymphoblastic Lymphoma
Abstract: While outcome for pediatric T lymphoblastic lymphoma (T-LBL) has improved with Acute Leukemia-type therapy, survival after relapse remains rare. Few prognostic markers have been identified and the value of Minimal Residual Disease (MRD) is less clear than in T-ALL. Mutations ofNOTCH1and/orFBXW7(N/F) identify good prognosis T-LBL and both MRD and high-level Minimal Disseminated Disease (MDD) are reported to be of poor prognosis. We evaluated MDD status by 8-color flow cytometry (MFC) and/or digital droplet PCR (ddPCR) in 86 French pediatric T-LBL, of whichN/Fstatus was known for 65 (61 treated on the Euro-LB02 protocol). Both techniques gave identical results for MDD/MRD values above 0.1%, allowing compilation. While an MDD threshold of 1% had no prognostic significance, the 54% (44/82) of protocol-treated patients with MDD ≥0.1% had a relatively favorable outcome (overall survival/OS; p = 0.026). MDD 0.1% status had no prognostic significance in the 68% of patients withN/Fmutations, whereas low/negative MDD status (9/61) identifiedN/Fgermline patients at a high risk of relapse (5-year OS of 44.4% vs 90% for MDD ≥ 0.1%,p = 0.014; and a 5-year DFS of 50% vs 90.9% respectively, p = 0.041). Combining oncogenetic and MDD status allows identification of 85% of patients with an excellent outcome (5-year OS 91.9% and DFS 95%) and 15% ofN/Fgermline/MDD< 0.1% patients who clearly require early alternative treatment (5-year OS 44.4%; p< 0.0001 and DFS 50%; p = 0.0001).
Published: 2020

15. Oncogenetic Landscape Of Lymphomagenesis In Coeliac Disease

Author: Thierry Jo Molina, Ludovic Lhermitte, Christine Bole-Feysot, Georgia Malamut, Elizabeth Macintyre, Morgane Cheminant, Amélie Trinquand, Sophie Kaltenbach, Bruno Tesson, Olivier Hermine, David Sibon, Sofia Berrabah, Patrick Villarese, Christophe Cellier, Sherine Khater, Nicolas Guegan, Sascha Cording, Julie Bruneau, Marc Bras, Bertrand Meresse, Nadine Cerf-Bensussan, Vahid Asnafi, and Michael Dussiot
Subjects: Bortezomib, medicine, Cancer research, Proteasome inhibitor, Biology, medicine.disease, DDX3X, TNFAIP3, Coeliac disease, Exome sequencing, Comparative genomic hybridization, medicine.drug, Lymphoma
Abstract: ObjectiveEnteropathy-associated T-cell lymphoma (EATL) is a rare but severe complication of celiac disease (CeD), often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII). Knowledge on underlying oncogenic mechanisms remains scarce. Here, we analysed and compared the mutational landscape of RCDII and EATL in order to identify genetic drivers of CeD-associated lymphomagenesis.DesignPure populations of RCDII-cells derived from intestinal biopsies (n=9) or sorted from blood (n=2) were analysed by whole exome sequencing, comparative genomic hybridization and RNA-sequencing. Biopsies from RCDII (n=50), EATL (n=19), type I refractory CeD (n=7) and uncomplicated CeD (n=7) were analysed by targeted next-generation sequencing. Moreover, functional in vitro studies and drug testing were performed in RCDII-derived cell lines.Results80% of RCDII and 90% of EATL displayed somatic gain-of-functions mutations in the JAK1-STAT3 pathway, including a remarkable p.G1097 hotspot mutation in the JAK1 kinase-domain in approximately 50% of cases. Other recurrent somatic events were deleterious mutations in NFκB-regulators TNFAIP3 and TNIP3 and potentially oncogenic mutations in TET2, KMT2D and DDX3X. JAK1 inhibitors and the proteasome inhibitor bortezomib could block survival and proliferation of malignant RCDII-cell lines.ConclusionMutations activating the JAK1-STAT3 pathway appear to be the main drivers of CeD-associated lymphomagenesis. In concert with mutations in negative regulators of NFκB, they may favour the clonal emergence of malignant lymphocytes in the cytokine-rich coeliac intestine. The identified mutations are attractive therapeutic targets to treat RCDII and block progression towards EATL.
Published: 2020

16. Rôle du pathologiste dans le diagnostic de la maladie cœliaque et de ses complications

Author: Julie Bruneau, David Sibon, Olivier Hermine, Christophe Cellier, Thierry Molina, Elizabeth Macintyre, Sherine Khater, Amélie Trinquand, Georgia Malamut, Nadine Cerf-Bensussan, Morgane Cheminant, and Danielle Canioni
Subjects: 0301 basic medicine, 03 medical and health sciences, Medical Laboratory Technology, 030104 developmental biology, 0302 clinical medicine, Biochemistry (medical), 030211 gastroenterology & hepatology, Analytical Chemistry
Abstract: Resume La maladie cœliaque (MC), ou intolerance au gluten, est une pathologie multifactorielle developpee sur un terrain genetique predisposant. Aujourd’hui encore sous diagnostiquee, elle toucherait pres de 1 % de la population mondiale. La presentation clinique classique d’enteropathie avec malabsorption n’est pas la plus frequente, elle est souvent asymptomatique, pauci-symptomatique ou de presentation clinique atypique. Son diagnostic est multidisciplinaire, et l’apport de l’histologie bien que discute, est souvent primordial, confirmant le diagnostic suspecte de MC et justifiant ainsi la mise en place d‘un regime sans gluten (RSG) a vie. L’histologie est utile egalement lors du suivi de la MC, afin de mettre en evidence une pathologie associee ou une evolution defavorable vers une MC refractaire au RSG. Enfin, il faut savoir remettre en question le diagnostic de MC si tous les parametres biologiques ne sont pas reunis et notamment un typage HLA compatible. En effet, la premiere cause d’atrophie villositaire est la MC, mais de nombreuses etiologies peuvent etre associees a une atrophie villositaire. Dans cette revue, les points essentiels du diagnostic, de la physiopathologie, de l’histopathologie et des complications de la MC seront developpes.
Published: 2018

17. NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: A CELAC study

Author: Nicolas Guegan, Florence Lhospice, Sascha Cording, Amélie Trinquand, Julie Bruneau, Olivier Hermine, Virginie Verkarre, Nicole Brousse, Christophe Cellier, Georgia Malamut, Elizabeth Macintyre, Felipe Suarez, Laurent Frenzel, Vahid Asnafi, Morgane Cheminant, Sherine Khater, Bertrand Meresse, Ambroise Marçais, Nadine Cerf-Bensussan, Tom van Gils, Chris J. J. Mulder, Thierry Jo Molina, Ludovic Lhermitte, C. cile Bonnafous, David Sibon, Anne-Sophie Jannot, Richard Delarue, Laurent Pouyet, Gastroenterology and hepatology, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Département de Pathologie [CHU Necker], Université Sorbonne Paris Cité (USPC)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), VU University Medical Center [Amsterdam], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University Paris Descartes Sorbonne Paris Cité, Imagine Institute, Paris, Mi-mAbs (C/O CIML), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Innate Pharma, Service de gastroenterologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques = Molecular mechanisms of hematological disorders and therapeutic implications (ERL 8254), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, MESH: Biopsy / methods, Enteropathy-Associated T-Cell Lymphoma / diagnosis, Entropathy-Associated T-Cell Lymphoma / etiology, Enteropathy-Associated T-Cell Lymphoma / immunology, T cell, Biopsy, [SDV.CAN]Life Sciences [q-bio]/Cancer, Coeliac Disease, Coeliac disease, 03 medical and health sciences, 0302 clinical medicine, Enteropathy-Associated T-Cell Lymphoma, Intestinal mucosa, Intestine, Small, medicine, Cytotoxic T cell, Humans, Intestinal Mucosa, MESH: Enteropathy-Associated T-Cell Lymphoma / pathology, Intestinal Mucosa / immunology, Intestinal Mucosa / pathology, Killer Cells, Natural / immunology, Antibody Targeted Therapy, Cells, Cultured, business.industry, Natural Cytotoxicity Triggering Receptor 1, Gastroenterology, MESH: Natural Cytotoxicity Triggering Receptor 1 / immunology, Antibodies, Monoclonal, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Middle Aged, medicine.disease, NKG2D, Prognosis, 3. Good health, Killer Cells, Natural, Celiac Disease, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Intraepithelial lymphocyte, Enteropathy-associated T-cell lymphoma, Female, France, Gastrointestinal Lymphoma, business, Ex vivo, Biomarkers, Tumour markers
Abstract: ObjectivesPrimary GI T-cell lymphoproliferative diseases (T-LPD) are heterogeneous entities, which raise difficult diagnosis and therapeutic challenges. We have recently provided evidences that lymphomas complicating coeliac disease (CD) arise from innate-like lymphocytes, which may carry NK receptors (NKRs).DesignNKRs expression was compared by flow cytometry in intraepithelial lymphocytes (IEL) from CD, type I or type II refractory CD (RCD). NKp46 was next assessed by immunohistochemistry in paraffin-embedded biopsies from 204 patients with CD, RCDI, RCDII or GI T-cell lymphomas and from a validation cohort of 61 patients. The cytotoxic properties of an anti-NKp46 monoclonal antibody conjugated to pyrrolobenzodiazepine (PBD) was tested ex vivo in human primary tumour cells isolated from fresh duodenal biopsies.ResultsNKp46 (but not CD94, NKG2A, NKG2C, NKG2D) was significantly more expressed by malignant RCDII IEL than by normal IEL in CD and RCDI. In paraffin biopsies, detection of >25 NKp46+ IEL per 100 epithelial cells discriminated RCDII from CD and RCDI. NKp46 was also detected in enteropathy-associated T-cell lymphomas (EATL, 24/29) and in monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL, 4/4) but not in indolent T-LPD (0/15). Treatment with anti-NKp46-PBD could efficiently and selectively kill human NKp46+ primary IEL ex vivo.ConclusionNKp46 is a novel biomarker useful for diagnosis and therapeutic stratification of GI T-LPD. Strong preclinical rationale identifies anti-NKp46-PBD as a promising therapy for RCDII, EATL and MEITL.
Published: 2019

18. Loss of ARHGEF1 causes a human primary antibody deficiency

Author: Anne Durandy, Sébastien Lofek, Hicham Lamrini, Eric Oksenhendler, Loic Chentout, Isabelle André-Schmutz, Elizabeth Macintyre, Sven Kracker, Marie-Céline Deau, Marc Bras, Lucie Heurtier, Amélie Trinquand, Marina Cavazzana, Amine Bouafia, Véronique Meignin, Olivier Alibeu, Alain Fischer, Julie Bruneau, Thierry Jo Molina, Capucine Picard, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Laboratoire d'Anatomie Pathologique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Génétique Humaine des Maladies Infectieuses (Inserm U980), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de bioinformatique (UNIV Paris Descartes), Université Paris Descartes - Paris 5 (UPD5), Hôpital Hôtel Dieu, Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Developpement Normal et Pathologique du Système Immunitaire, Service d'Immunopathologie Clinique, ANR-15-CE15-0020,PIKimun,Caractérisation de la voie PI3K / AKT / mTOR - dans les lymphocytes humains(2015), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Chaire Médecine expérimentale (A. Fischer), and Collège de France (CdF (institution))
Subjects: 0301 basic medicine, Male, RHOA, Primary Immunodeficiency Diseases, T-Lymphocytes, [SDV]Life Sciences [q-bio], GTP-Binding Protein alpha Subunits, G12-G13, 03 medical and health sciences, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, medicine, Humans, Lymphocytes, Protein kinase B, PI3K/AKT/mTOR pathway, B cell, ComputingMilieux_MISCELLANEOUS, B-Lymphocytes, rho-Associated Kinases, [SDV.GEN]Life Sciences [q-bio]/Genetics, biology, Chemistry, Siblings, Germinal center, General Medicine, Marginal zone, Actin cytoskeleton, Germinal Center, Molecular biology, 3. Good health, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, biology.protein, Commentary, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, rhoA GTP-Binding Protein, Immunologic Memory, Proto-Oncogene Proteins c-akt, Rho Guanine Nucleotide Exchange Factors, Research Article, Signal Transduction
Abstract: ARHGEF1 is a RhoA-specific guanine nucleotide exchange factor expressed in hematopoietic cells. We used whole-exome sequencing to identify compound heterozygous mutations in ARHGEF1, resulting in the loss of ARHGEF1 protein expression in 2 primary antibody–deficient siblings presenting with recurrent severe respiratory tract infections and bronchiectasis. Both ARHGEF1-deficient patients showed an abnormal B cell immunophenotype, with a deficiency in marginal zone and memory B cells and an increased frequency of transitional B cells. Furthermore, the patients’ blood contained immature myeloid cells. Analysis of a mediastinal lymph node from one patient highlighted the small size of the germinal centers and an abnormally high plasma cell content. On the molecular level, T and B lymphocytes from both patients displayed low RhoA activity and low steady-state actin polymerization (even after stimulation of lysophospholipid receptors). As a consequence of disturbed regulation of the RhoA downstream target Rho-associated kinase I/II (ROCK), the patients’ lymphocytes failed to efficiently restrain AKT phosphorylation. Enforced ARHGEF1 expression or drug-induced activation of RhoA in the patients’ cells corrected the impaired actin polymerization and AKT regulation. Our results indicate that ARHGEF1 activity in human lymphocytes is involved in controlling actin cytoskeleton dynamics, restraining PI3K/AKT signaling, and confining B lymphocytes and myelocytes within their dedicated functional environment.
Published: 2019

19. Standardization of Flow Cytometric Immunophenotyping for Hematological Malignancies: The FranceFlow Group Experience

Author: Carmen Mariana Aanei, Hind Bennami, Victoria Raggeneau, Chantal Brouzes, Françoise Solly, Lydia Campos, Amélie Trinquand, Nicolas Neyman, Ludovic Lhermitte, Vahid Asnafi, Caroline Mayeur-Rousse, Agathe Debliquis, Anne Roggy, Frédéric Massin, Adriana Plesa, Myrto Costopoulos, Anne-Catherine Lhoumeau, Hugues Jacqmin, Fanny Angelot-Delettre, Soraya Wuilleme, Elodie Lainey, Nelly Robillard, Sébastien Lachot, Coralie Derrieux, Lucile Baseggio, Alice Eischen, Francine Garnache-Ottou, Alessandra Rosenthal-Allieri, Mickael Roussel, Hubert Rambaud, Elisabeth Andre-Kerneis, Christine Arnoulet, Magali Le Garff-Tavernier, Véronique Salaun, Michel Ticchioni, Edouard Cornet, Marie-Thérèse Georget, Franck Geneviève, Marie-Christine Jacob, Véronique Latger-Cannard, Maxime Maurer, UCL - SSS/IREC/MONT - Pôle Mont Godinne, and UCL - (MGD) Département de pharmacie
Subjects: 0301 basic medicine, Quality Control, medicine.medical_specialty, Histology, Standardization, quality controls, Fluorescence, Monocytes, Pathology and Forensic Medicine, Immunophenotyping, 03 medical and health sciences, 0302 clinical medicine, Belgium, immunophenotyping, EuroFlow, Internal medicine, medicine, Humans, Lymphocytes, Protocol (science), standardization, Reproducibility, business.industry, hematology, flow cytometry, Reproducibility of Results, Cell Biology, Reference Standards, Flow Cytometry, Clinical trial, 030104 developmental biology, instrument settings, 030220 oncology & carcinogenesis, Hematologic Neoplasms, France, FranceFlow, business, Cytometry, Companion diagnostic
Abstract: Flow cytometry is broadly used for the identification, characterization, and monitoring of hematological malignancies. However, the use of clinical flow cytometry is restricted by its lack of reproducibility across multiple centers. Since 2006, the EuroFlow consortium has been developing a standardized procedure detailing the whole process from instrument settings to data analysis. The FranceFlow group was created in 2010 with the intention to educate participating centers in France about the standardized instrument setting protocol (SOP) developed by the EuroFlow consortium and to organise several rounds of quality controls (QCs) in order to evaluate the feasibility of its application and its results. Here, we report the 5 year experience of the FranceFlow group and the results of the seven QCs of 23 instruments, involving up to 19 centers, in France and in Belgium. The FranceFlow group demonstrates that both the distribution and applicability of the SOP have been successful. Intercenter reproducibility was evaluated using both normal and pathological blood samples. Coefficients of variation (CVs) across the centers were
Published: 2019

20. Response to 5-azacytidine in a patient with TET2 -mutated angioimmunoblastic T-cell lymphoma and chronic myelomonocytic leukaemia preceded by an EBV-positive large B-cell lymphoma

Author: Thierry Jo Molina, Julie Bruneau, Vahid Asnafi, Elizabeth Macintyre, Hélène Guermouche, Richard Delarue, Ludovic Lhermitte, Lucile Couronné, Olivier Hermine, Olivier Kosmider, Colombe Saillard, Coralie Derrieux, Morgane Cheminant, Felipe Suarez, Laurent Frenzel, Amélie Trinquand, and François Lemonnier
Subjects: 0301 basic medicine, Neuroblastoma RAS viral oncogene homolog, Cancer Research, Angioimmunoblastic T-cell lymphoma, Myeloid, IDH1, Azacitidine, Hematology, General Medicine, Biology, medicine.disease, Lymphoma, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Oncology, hemic and lymphatic diseases, 030220 oncology & carcinogenesis, Immunology, medicine, Progenitor cell, B-cell lymphoma, medicine.drug
Abstract: We report the case of a patient with a history of Epstein-Barr virus-positive large B-cell lymphoma, who relapsed with an angioimmunoblastic T-cell lymphoma (AITL) associated with a chronic myelomonocytic leukaemia (CMML). We performed targeted next-generation sequencing on CMML and AITL DNA, which revealed mutations of TET2, DNMT3A, SRSF2, NRAS and IDH1, thus confirming that the spectrum of AITL mutations share similarities with myeloid disorders. The frequencies of TET2/DNMT3A and SRSF2 variants could support the hypothesis that TET2/DNMT3A mutations occurred in an early progenitor cell, which later progressed to both the AITL and CMML clones. Treatment with 5-azacytidine led to the complete remission of both diseases. Thus, targeting DNA methylation abnormalities in AITL may be an alternative strategy to chemotherapy. Copyright © 2016 John Wiley & Sons, Ltd.
Published: 2016

21. Early thymic precursor-like lymphomatous presentation of theETV6-NCOA2translocation

Author: Jonathan Bond, Amélie Trinquand, Jean-Louis Stephan, Elizabeth Macintyre, Sandrine Thouvenin, Isabelle Radford-Weiss, Nathalie Nadal, Vanessa Da Cruz, Pierre-Emmanuel Bonté, Aurore Touzart, and Nathalie Garnier
Subjects: Pathology, medicine.medical_specialty, business.industry, Chromosomal translocation, Hematology, medicine.disease, Lymphoma, 03 medical and health sciences, ETV6, 0302 clinical medicine, 030220 oncology & carcinogenesis, Medicine, Presentation (obstetrics), business, 030215 immunology
Published: 2017

22. A Single-Tube, EuroClonality-Inspired, TRG Clonality Multiplex PCR Aids Management of Patients with Enteropathic Diseases, including from Formaldehyde-Fixed, Paraffin-Embedded Tissues

Author: Olivier Hermine, Nadine Cerf-Bensussan, Virginie Verkarre, Bertrand Meresse, Thierry Jo Molina, Nicole Brousse, Amélie Trinquand, Coralie Derrieux, Julie Bruneau, Georgia Malamut, Christophe Cellier, Elizabeth Macintyre, Patrick Villarese, David Sibon, Marion Alcantara, and Ludovic Lhermitte
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Tissue Fixation, Lymphoproliferative disorders, Lymphoma, T-Cell, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Immunophenotyping, Formaldehyde, Multiplex polymerase chain reaction, medicine, Humans, Multiplex, Prospective Studies, Gene Rearrangement, Paraffin Embedding, business.industry, Gene rearrangement, medicine.disease, Lymphoma, Celiac Disease, 030104 developmental biology, 030220 oncology & carcinogenesis, Molecular Medicine, Immunohistochemistry, Intraepithelial lymphocyte, business, Multiplex Polymerase Chain Reaction
Abstract: Celiac disease is a chronic inflammation of the small intestine with villous atrophy that can become refractory to a gluten-free diet. Two categories of refractory celiac disease can be distinguished by the phenotype of intraepithelial lymphocytes and the status of TRG genes. Their distinction is important because 30% to 50% of type II but only 0% to 14% of type I evolve to an aggressive enteropathy-associated T-cell lymphoma and therefore require intensive treatment. Currently, differential diagnosis integrates immunohistochemistry, immunophenotyping, and TRG clonality analyses, but each has limitations. A single-tube multiplex TRG PCR (ECN) was prospectively compared to an in-house two-tube TRG PCR (N2T) in 73 samples, including 67 cryopreserved intestine tissues. Thirteen formalin-fixed, paraffin-embedded (FFPE) samples were also analyzed retrospectively. The ECN PCR had comparable efficiency to detect major clonal rearrangements in highly infiltrated tissues from T-cell lymphoproliferative disorders and type II refractory celiac disease and to detect the persistence of minor clones in type II refractory celiac disease follow-up samples. The ECN PCR abolished the risk of amplification of false-positive weak clonal rearrangements in cryopreserved specimens and allowed improved detection of clonal rearrangements in DNA from FFPE samples. The ECN PCR allows robust assessment of cryopreserved and FFPE digestive tissues at diagnosis and follow-up of enteropathies with villous atrophy, thus guiding therapeutic management.
Published: 2018

23. Les mutations oncogénétiques associées à la MRD améliorent la prédiction du risque de rechute des leucémies aiguës lymphoblastiques T pédiatriques

Author: Gérard Michel, Jean Soulier, Sandrine Thouvenin, André Baruchel, Judith Landman-Parker, Nathalie Grardel, Paola Ballerini, Sylvie Chevret, Aurore Touzart, Guy Leverger, Elizabeth Macintyre, Claude Preudhomme, Arnaud Petit, Jean-Michel Cayuela, Vahid Asnafi, Amélie Trinquand, Hélène Lapillonne, Claudine Schmitt, Benoit Brethon, Sorbonne Université (SU), Hôpital Necker, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Lille, AP-HP Hôpital universitaire Robert-Debré [Paris], Centre Hospitalier Universitaire de Nancy (CHU Nancy), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and Assistance Publique - Hôpitaux de Marseille (APHM)
Subjects: 0301 basic medicine, medicine.medical_specialty, Neoplasm, Residual, Adolescent, Lymphoblastic Leukemia, T cell, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Biochemistry, Gastroenterology, Disease-Free Survival, Leukocyte Count, 03 medical and health sciences, 0302 clinical medicine, Recurrence, hemic and lymphatic diseases, White blood cell, Internal medicine, medicine, Humans, PTEN, Cumulative incidence, Child, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, biology, business.industry, Proportional hazards model, Infant, Newborn, Infant, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Oncogenes, Cell Biology, Hematology, Stepwise regression, Prognosis, Minimal residual disease, Treatment Outcome, 030104 developmental biology, medicine.anatomical_structure, Child, Preschool, 030220 oncology & carcinogenesis, Mutation, biology.protein, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genes, Neoplasm
Abstract: Risk stratification in childhood T-cell acute lymphoblastic leukemia (T-ALL) is mainly based on minimal residual disease (MRD) quantification. Whether oncogenetic mutation profiles can improve the discrimination of MRD-defined risk categories was unknown. Two hundred and twenty FRALLE2000T-treated patients were tested retrospectively for NOTCH1/FBXW7/RAS and PTEN alterations. Patients with NOTCH1/FBXW7 (N/F) mutations and RAS/PTEN (R/P) germ line (GL) were classified as oncogenetic low risk (gLoR; n = 111), whereas those with N/F GL and R/P GL mutations or N/F and R/P mutations were classified as high risk (gHiR; n = 109). Day 35 MRD status was available for 191 patients. Five-year cumulative incidence of relapse (CIR) and disease-free survival were 36% and 60% for gHiR patients and 11% and 89% for gLoR patients, respectively. Importantly, among the 60% of patients with MRD
Published: 2018

24. Monitoring molecular response in adult T-cell leukemia by high-throughput sequencing analysis of HTLV-1 clonality

Author: Felipe Suarez, Amélie Trinquand, Maria Artesi, Arsène Burny, Michel Georges, Ambroise Marçais, Ludovic Lhermitte, Nicolas Rosewick, Vincent Hahaut, Véronique Avettand-Fenoel, A. Van den Broeke, Vahid Asnafi, Olivier Hermine, Keith Durkin, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Institut Jules Bordet, Groupe Interdisciplinaire de Génoprotéomique Appliquée ( GIGA-Research ), Université de Liège-Faculté de médecine vétérinaire, Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Protein Signaling and Interactions - GIGA Research Center, Université de Liège-Department of Chemistry - Gembloux ABT, and CHU Necker - Enfants Malades [AP-HP]
Subjects: Adult, Male, 0301 basic medicine, Cancer Research, Leukemia lymphoma, T-cell leukemia, DNA sequencing, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, hemic and lymphatic diseases, medicine, Humans, Leukemia-Lymphoma, Adult T-Cell, Longitudinal Studies, Letter to the Editor, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Human T-lymphotropic virus 1, biology, High-Throughput Nucleotide Sequencing, Généralités, Hematology, Middle Aged, biology.organism_classification, medicine.disease, HTLV-I Infections, Virology, Molecular biology, Leukemia, 030104 developmental biology, Oncology, Molecular Response, HTLV-I infections, Female
Abstract: SCOPUS: le.j, info:eu-repo/semantics/published
Published: 2017

25. TCRα rearrangements identify a subgroup of NKL-deregulated adult T-ALLs associated with favorable outcome

Author: Mohamed Belhocine, Audrey Petit, Patrick Villarese, S Le Noir, C Lours, Anthonie Willem Langerak, M. Tesio, M. Lelorc’h, A Cieslak, Vahid Asnafi, Norbert Ifrah, Elizabeth Macintyre, Nicolas Boissel, Salvatore Spicuglia, Ludovic Lhermitte, Amélie Trinquand, Hervé Dombret, Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Technologies avancées pour le génôme et la clinique ( TAGC ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Immunology
Subjects: Adult, Male, 0301 basic medicine, Cancer Research, Lineage (genetic), Receptors, Antigen, T-Cell, alpha-beta, T cell, Cellular differentiation, [SDV]Life Sciences [q-bio], Biology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, 03 medical and health sciences, Antigen, Cell Line, Tumor, medicine, Humans, Leukemia-Lymphoma, Adult T-Cell, Receptor, Gene, ComputingMilieux_MISCELLANEOUS, Homeodomain Proteins, [ SDV ] Life Sciences [q-bio], T-cell receptor, Cell Differentiation, Receptors, Antigen, T-Cell, gamma-delta, Hematology, Molecular biology, 030104 developmental biology, medicine.anatomical_structure, Oncology, Female, Ectopic expression, HeLa Cells
Abstract: T-cell acute lymphoblastic leukemia (T-ALL) results from leukemic transformation of T-cell precursors arrested at specific differentiation stages, including an 'early-cortical' thymic maturation arrest characterized by expression of cytoplasmic TCRβ but no surface T-cell receptor (TCR) and frequent ectopic expression of the TLX1/3 NK-like homeotic proteins (NKL). We designed a TCRα VJC PCR to identify clonal TCRα rearrangements in 32% of 127 T-ALLs, including 0/52 immature/TCRγδ lineage cases and 41/75 (55%) TCRαβ lineage cases. Amongst the latter, TCRα rearrangements were not identified in 30/54 (56%) of IMβ/pre-αβ early-cortical T-ALLs, of which the majority (21/30) expressed TLX1/3. We reasoned that the remaining T-ALLs might express other NKL proteins, so compared transcript levels of 46 NKL in T-ALL and normal thymic subpopulations. Ectopic overexpression of 10 NKL genes, of which six are unreported in T-ALL (NKX2-3, BARHL1, BARX2, EMX2, LBX2 and MSX2), was detectable in 17/104 (16%) T-ALLs. Virtually all NKL overexpressing T-ALLs were TCRα unrearranged and ectopic NKL transcript expression strongly repressed Eα activity, suggesting that ectopic NKL expression is the major determinant in early-cortical thymic T-ALL maturation arrest. This immunogenetic T-ALL subtype, defined by TCRβ VDJ but no TCRα VJ rearrangement, is associated with a favorable outcome in GRAALL-treated adult T-ALLs.
Published: 2017

26. An unusual case of acute leukemia

Author: Madalina Uzunov, Myrto Costopoulos, Catherine Settegrana, Amélie Trinquand, Laurence Simon, Ines Safra Zaghouani, Magali Le Garff-Tavernier, Marie Passet, Marine Armand, Elise Chapiro, Carole Fleury, Service de parasitologie - mycologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Laboratoire d'Hématologie, CHU Strasbourg, Service d'hématologie biologique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'Hématologie Clinique [CHU Pitié-Salpêtrière], Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie biologique [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Adult, Male, 030213 general clinical medicine, Myeloid, medicine.medical_treatment, T-Lymphocytes, Population, Hematopoietic stem cell transplantation, Immunophenotyping, 03 medical and health sciences, 0302 clinical medicine, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, hemic and lymphatic diseases, Medicine, Humans, Myeloid Cells, education, Chemotherapy, education.field_of_study, Acute leukemia, B-Lymphocytes, Leukemia, business.industry, flow cytometry, T-cell receptor, acute lymphoblastic T-cell leukemia, lymphoid clonality, General Medicine, Minimal residual disease, mixed phenotype acute leukemia, 3. Good health, Leukemia, Biphenotypic, Acute, medicine.anatomical_structure, Acute Disease, cytology, Cancer research, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; We report the case of a 31 year-old man diagnosed with an atypical acute leukemia difficult to characterize cytologically. The immunophenotyping identified a blastic population co-expressing myeloid, lymphoidBand lymphoid T markers suggesting the diagnosis of either a mixed phenotype acute leukemia (MPAL) or an early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Because of the poor prognosis linked to these leukemias, the patient benefited from chemotherapy targeting both myeloid and lymphoid components, followed by allogeneic hematopoietic stem cell transplantation. DNA-based techniques analyzing B and T-cell clonality identified partial rearrangements in immunoglobulin and TCR genes, allowing the monitoring of minimal residual disease. This observation highlights the difficulty to classify some atypical cases of acute leukemias. It emphasizes on the complementarity of cytomorphology, immunophenotyping by flow cytometry and molecular techniques in order to promptly characterize and treat these leukemias.
Published: 2017

27. Age-related clinical and biological features of PTEN abnormalities in T-cell acute lymphoblastic leukaemia

Author: Paola Ballerini, Amélie Trinquand, Hervé Dombret, Melania Tesio, Vahid Asnafi, Arnaud Petit, Elisabeth Macintyre, Ludovic Lhermitte, Norbert Ifrah, André Baruchel, Guillaume Hypolite, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Pôle de Recherche et d’Enseignement Supérieur [LUNAM], PRES Université Nantes Angers Le Mans (UNAM), Service des maladies du sang [CHU Angers], PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service d'hématologie et immunologie pédiatrique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hopital Saint-Louis [AP-HP] (AP-HP), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), AT was supported by a grant from INCa (Institut National du Cancer: «Soutien à la Recherche Translationnelle 2012»). MT was supported by Grants from Fondation de France (FdF) and Fondation pour la recherche sur le Cancer (ARC). This work was supported by grants from the ‘La Ligue Contre le Cancer’ and the ‘Association Laurette Fugain’., Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), and Bernardo, Elizabeth
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, Pathology, Oncogene Proteins, Fusion, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Workflow, Immunophenotyping, Medicine, Young adult, Child, Sequence Deletion, Comparative Genomic Hybridization, biology, Age Factors, High-Throughput Nucleotide Sequencing, Exons, Hematology, Middle Aged, Prognosis, 3. Good health, Child, Preschool, Cohort, Female, Abnormality, Adult, medicine.medical_specialty, Adolescent, [SDV.CAN]Life Sciences [q-bio]/Cancer, Young Adult, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Biomarkers, Tumor, Humans, PTEN, Genetic Predisposition to Disease, Allele, Alleles, Genetic Association Studies, Survival analysis, business.industry, PTEN Phosphohydrolase, Genetic Variation, Infant, Survival Analysis, 030104 developmental biology, biology.protein, business, Comparative genomic hybridization
Abstract: International audience; The tumour suppressor gene PTEN is commonly altered in T-cell acute lymphoblastic leukaemia but its prognostic impact is still debated. We screened a cohort of 573 fully characterised adult and paediatric T-cell acute lymphoblastic leukaemia (TALL) patients for genomic PTEN abnormalities. PTEN-inactivating mutations and/or deletions were identified in 91 cases (16%), including 18% of paediatric (49/277) and 14% of adult cases (42/296). Thirty-four patients harboured only mutations, 12 cases demonstrated only large deletions and 9 only microdeletions. About 36 patients had combined alterations. Different mechanisms of PTEN inactivation predicted differences in the clinical outcome for both adult and paediatric patients treated according to the GRAALL03/05 and FRALLE2000 protocols. Whereas large deletions predicted lower 5-year overall survival (P = 0.0053 in adults, P = 0.001 in children) and disease-free survival (P = 0.0009 in adults, P = 0.0002 in children), mutations were not associated with a worse prognosis. The prognostic impact of PTEN loss is therefore linked to the underlying type of genomic abnormality, both in adult and paediatric T-ALLs, demonstrating that detailed analysis of the type of abnormality type would be useful to refine risk stratification.
Published: 2017

28. Quality assessment program for EuroFlow protocols: Summary results of four-year (2010-2013) quality assurance rounds

Author: Sebastian Böttcher, Vincent H.J. van der Velden, Vahid Asnafi, Alita J. van der Sluijs-Gelling, Marta Martin-Ayuso, Quentin Lecrevisse, Paola Bonaccorso, Anton W. Langerak, Tomas Kalina, Tomasz Szczepański, Łukasz Sędek, Dennis Karsch, Alberto Orfao, Ester Mejstrikova, Margarida Lima, Nancy Boeckx, Michaela Novakova, Paulo Sérgio Lucio, Juan Flores-Montero, Jacques J.M. van Dongen, Joana Caetano, Amélie Trinquand, Carlos E. Pedreira, Ondrej Hrusak, and Ana Helena Santos
Subjects: medicine.medical_specialty, Histology, Standardization, Quality assessment, business.industry, Computer science, Coefficient of variation, Cell Biology, Disease monitoring, Pathology and Forensic Medicine, EuroFlow, Reference values, Immunology, medicine, Medical physics, business, Quality assurance, Lymphocyte subsets
Abstract: Flow cytometric immunophenotyping has become essential for accurate diagnosis, classification, and disease monitoring in hemato-oncology. The EuroFlow Consortium has established a fully standardized "all-in-one" pipeline consisting of standardized instrument settings, reagent panels, and sample preparation protocols and software for data analysis and disease classification. For its reproducible implementation, parallel development of a quality assurance (QA) program was required. Here, we report on the results of four consecutive annual rounds of the novel external QA EuroFlow program. The novel QA scheme aimed at monitoring the whole flow cytometric analysis process (cytometer setting, sample preparation, acquisition and analysis) by reading the median fluorescence intensities (MedFI) of defined lymphocytes' subsets. Each QA participant applied the predefined reagents' panel on blood cells of local healthy donors. A uniform gating strategy was applied to define lymphocyte subsets and to read MedFI values per marker. The MedFI values were compared with reference data and deviations from reference values were quantified using performance score metrics. In four annual QA rounds, we analyzed 123 blood samples from local healthy donors on 14 different instruments in 11 laboratories from nine European countries. The immunophenotype of defined cellular subsets appeared sufficiently standardized to permit unified (software) data analysis. The coefficient of variation of MedFI for 7 of 11 markers performed repeatedly below 30%, average MedFI in each QA round ranged from 86 to 125% from overall median. Calculation of performance scores was instrumental to pinpoint standardization failures and their causes. Overall, the new EuroFlow QA system for the first time allowed to quantify the technical variation that is introduced in the measurement of fluorescence intensities in a multicentric setting over an extended period of time. EuroFlow QA is a proficiency test specific for laboratories that use standardized EuroFlow protocols. It may be used to complement, but not replace, established proficiency tests. © 2014 International Society for Advancement of Cytometry.
Published: 2014

29. RAS-associated lymphoproliferative disease evolves into severe juvenile myelo-monocytic leukemia

Author: Felipe Suarez, Marie-Claude Stolzenberg, Nina Lanzarotti, Eva Lévy, Frédéric Rieux-Laucat, Amélie Trinquand, Hélène Cavé, Bénédicte Neven, Nizar Mahlaoui, Nadia Jeremiah, Aude Magerus-Chatinet, Alain Fischer, Julie Bruneau, and Julien Fregeac
Subjects: MAPK/ERK pathway, Juvenile myelomonocytic leukemia, Somatic cell, Immunology, Lymphoproliferative disorders, Cell Biology, Hematology, Biology, medicine.disease, Biochemistry, Leukemia, medicine, Monocytic leukemia, Juvenile, Lymphoproliferative disease
Abstract: To the editor: In juvenile myelomonocytic leukemia (JMML), activating RAS mutations are responsible for a hyperactive RAS/ERK signaling.[1][1] Somatic codons 12-13-61 RAS mutations are described in cases of RAS -associated lymphoproliferative disease (RALD),[2][2][⇓][3]-[4][4] believed to be a
Published: 2014

30. Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia

Author: David-Alexandre Gross, Melania Tesio, Amélie Trinquand, Mohamed Belhocine, Hervé Dombret, Norbert Ifrah, Benedetta Zaniboni, Lucienne Chatenoud, Vahid Asnafi, Francesca Rocchetti, François-Loïc Cosset, Nuno R. dos Santos, Christine Tran Quang, Ludovic Lhermitte, Jacques Ghysdael, Elizabeth Macintyre, Michael Dussiot, Françoise Pflumio, Olivier Hermine, Els Verhoeyen, Cindy Da Costa de Jesus, Salvatore Spicuglia, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Algarve [Portugal], Stress génotoxiques et cancer, Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe 'Contrôle Métabolique des Morts Cellulaires' (INSERM U1065 - C3M), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Laboratoire de Recherche sur les Cellules Souches Hématopoiétiques et Leucémiques (LSHL), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Tolérance immunitaire et présentation antigénique: impact en auto-immunité et en transplantation, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Technologies avancées pour le génôme et la clinique ( TAGC ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratory of Excellence GR-Ex, Sorbonne Paris Cité-Université Paris Descartes - Paris 5 ( UPD5 ) -Imagine Institute, Centre International de Recherche en Infectiologie ( CIRI ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Boehringer Ingelheim RCV, Service de Chimie Moléculaire ( SCM ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ), Hematology Department, Université d'Angers ( UA ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers, Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Service d'hématologie-immunologie-oncologie pédiatrique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université Paris-Sud - Paris 11 (UP11)-Institut Curie-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (Equipe EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Paris-Sud - Paris 11 (UP11), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Leukemia, T-Cell, CD3 Complex, medicine.medical_treatment, CD3, T-Lymphocytes, [SDV]Life Sciences [q-bio], T-cell leukemia, Receptors, Antigen, T-Cell, Antigen-Presenting Cells, Apoptosis, Biology, Lymphocyte Activation, Targeted therapy, Immunophenotyping, 03 medical and health sciences, Mice, medicine, Animals, Humans, Clonal Selection, Antigen-Mediated, Mice, Knockout, [ SDV ] Life Sciences [q-bio], T-cell receptor, Antibodies, Monoclonal, medicine.disease, 3. Good health, Leukemia, Disease Models, Animal, 030104 developmental biology, Oncology, Tumor progression, Immunology, Cancer cell, biology.protein, Female, Signal Transduction
Abstract: Cancer onset and progression involves the accumulation of multiple oncogenic hits, which are thought to dominate or bypass the physiologic regulatory mechanisms in tissue development and homeostasis. We demonstrate in T-cell acute lymphoblastic leukemia (T-ALL) that, irrespective of the complex oncogenic abnormalities underlying tumor progression, experimentally induced, persistent T-cell receptor (TCR) signaling has antileukemic properties and enforces a molecular program resembling thymic negative selection, a major developmental event in normal T-cell development. Using mouse models of T-ALL, we show that induction of TCR signaling by high-affinity self-peptide/MHC or treatment with monoclonal antibodies to the CD3ϵ chain (anti-CD3) causes massive leukemic cell death. Importantly, anti-CD3 treatment hampered leukemogenesis in mice transplanted with either mouse- or patient-derived T-ALLs. These data provide a strong rationale for targeted therapy based on anti-CD3 treatment of patients with TCR-expressing T-ALL and demonstrate that endogenous developmental checkpoint pathways are amenable to therapeutic intervention in cancer cells. Significance: T-ALLs are aggressive malignant lymphoid proliferations of T-cell precursors characterized by high relapse rates and poor prognosis, calling for the search for novel therapeutic options. Here, we report that the lineage-specific TCR/CD3 developmental checkpoint controlling cell death in normal T-cell progenitors remains switchable to induce massive tumor cell apoptosis in T-ALL and is amenable to preclinical therapeutic intervention. Cancer Discov; 6(9); 972–85. ©2016 AACR. See related commentary by Lemonnier and Mak, p. 946. This article is highlighted in the In This Issue feature, p. 932
Published: 2016

31. NAP1L1-MLLT10 is a rare recurrent translocation that is associated with HOXA activation and poor treatment response in T-cell acute lymphoblastic leukaemia

Author: Aurore Touzart, Tony Marchand, Agata Cieslak, Marc Muller, Jonathan Bond, Elizabeth Macintyre, Martine Escoffre, Claudine Schmitt, Vahid Asnafi, Thierry Fest, Audrey Contet, Amélie Trinquand, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironnement et cancer (MiCa), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Unité de Transplantation Médullaire, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Hôpital d'enfants, Service de Médecine Nucléaire [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Hématologie Pédiatrique [CHRU Nancy], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), B, AT, AC, AT, MM and TF performed and interpreted diagnostic investigations. TM, ME, AC and CS provided clinical care and interpreted clinical data. JB, VA and EAM analysed and collated data and wrote the manuscript. JB is supported by a Kay Kendall Leukaemia Fund Intermediate Research Fellowship. The Macintyre laboratory is supported by the Association Laurette Fugain and the INCa CARAMELE Translational Research and PhD Programmes., Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Médecine Nucléaire [Nancy], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'hématologie ( ERL 8254 ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Microenvironnement et cancer ( MiCa ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Hôpital d'enfants, Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: 0301 basic medicine, acute leukaemia, Treatment response, NAP1L1, [SDV]Life Sciences [q-bio], MEDLINE, Chromosomal translocation, HOXA, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Text mining, Medicine, clinical aspects, Young adult, leukaemia cytogenetics, ComputingMilieux_MISCELLANEOUS, [ SDV ] Life Sciences [q-bio], business.industry, biology, T-cell acute lymphoblastic leukaemia, Hematology, 3. Good health, 030104 developmental biology, Cancer research, business, 030215 immunology
Abstract: International audience; no abstract
Published: 2016

32. An early thymic precursor phenotype predicts outcome exclusively in HOXA-overexpressing adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study

Author: Amélie Trinquand, Vahid Asnafi, Jonathan Bond, Elizabeth Macintyre, Aurore Touzart, Isabelle Radford-Weiss, Agata Cieslak, Norbert Ifrah, Salvatore Spicuglia, Hervé Dombret, Jean-François Hamel, Ludovic Lhermitte, Laurent Sutton, Tony Marchand, Kay Kendall Leukemia Fund, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lymphocyte et cancer, IFR105-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre de recherche clinique, PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Microenvironnement et cancer ( MiCa ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire d'hématologie ( ERL 8254 ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Technologies avancées pour le génôme et la clinique ( TAGC ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), IFR105-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Centre Hospitalier Universitaire d'Angers ( CHU Angers ), PRES Université Nantes Angers Le Mans ( UNAM ), CHU Angers-Centre hospitalier Universitaire Angers, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: 0301 basic medicine, Adult, Male, [SDV]Life Sciences [q-bio], Immunology, Gene Expression, Thymus Gland, HOXA, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, 1102 Cardiovascular Medicine And Haematology, Article, Immunophenotyping, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Recurrence, hemic and lymphatic diseases, Gene expression, Antineoplastic Combined Chemotherapy Protocols, Medicine, Cluster Analysis, Humans, Young adult, Regulation of gene expression, Homeodomain Proteins, [ SDV ] Life Sciences [q-bio], Cytogenetics and Molecular Genetics, business.industry, Gene Expression Profiling, Hematology, Middle Aged, Prognosis, Phenotype, Minimal residual disease, 3. Good health, Gene expression profiling, Gene Expression Regulation, Neoplastic, Adult Acute Lymphoblastic Leukemia, 030104 developmental biology, Treatment Outcome, 030220 oncology & carcinogenesis, Cancer research, Female, business, ETP-ALL
Abstract: International audience; Unlabelled - Gene expression studies have consistently identified a HOXA-overexpressing cluster of T-cell acute lymphoblastic leukemias, but it is unclear whether these constitute a homogeneous clinical entity, and the biological consequences of HOXA overexpression have not been systematically examined. We characterized the biology and outcome of 55 HOXA-positive cases among 209 patients with adult T-cell acute lymphoblastic leukemia uniformly treated during the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003 and -2005 studies. HOXA-positive patients had markedly higher rates of an early thymic precursor-like immunophenotype (40.8% versus 14.5%, P=0.0004), chemoresistance (59.3% versus 40.8%, P=0.026) and positivity for minimal residual disease (48.5% versus 23.5%, P=0.01) than the HOXA-negative group. These differences were due to particularly high frequencies of chemoresistant early thymic precursor-like acute lymphoblastic leukemia in HOXA-positive cases harboring fusion oncoproteins that transactivate HOXA Strikingly, the presence of an early thymic precursor-like immunophenotype was associated with marked outcome differences within the HOXA-positive group (5-year overall survival 31.2% in HOXA-positive early thymic precursor versus 66.7% in HOXA-positive non-early thymic precursor, P=0.03), but not in HOXA-negative cases (5-year overall survival 74.2% in HOXA-negative early thymic precursor versus 57.2% in HOXA-negative non-early thymic precursor, P=0.44). Multivariate analysis further revealed that HOXA positivity independently affected event-free survival (P=0.053) and relapse risk (P=0.039) of chemoresistant T-cell acute lymphoblastic leukemia. These results show that the underlying mechanism of HOXA deregulation dictates the clinico-biological phenotype, and that the negative prognosis of early thymic precursor acute lymphoblastic leukemia is exclusive to HOXA-positive patients, suggesting that early treatment intensification is currently suboptimal for therapeutic rescue of HOXA-positive chemoresistant adult early thymic precursor acute lymphoblastic leukemia. Trial registration - The GRAALL-2003 and -2005 studies were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.
Published: 2016

33. Receptor kinase profiles identify a rationale for multitarget kinase inhibition in immature T-ALL

Author: Ludovic Lhermitte, Marta Antonina Libura, Guy Leverger, Vincent Guillemot, Arnaud Petit, Vahid Asnafi, Elizabeth Macintyre, Patrick Villarese, A S Bedin, Norbert Ifrah, Hervé Dombret, N Bedjaoui, R. Ben Abdelali, Amélie Trinquand, Olivier Hermine, Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, Cancer Research, Adolescent, Apoptosis, Biology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Polymerase Chain Reaction, Young Adult, Tumor Cells, Cultured, Humans, Child, Receptor, Protein Kinase Inhibitors, ComputingMilieux_MISCELLANEOUS, Aged, Kinase, Infant, Receptor Protein-Tyrosine Kinases, Drug Synergism, DNA, Neoplasm, Hematology, Middle Aged, Kinase inhibition, Flow Cytometry, Prognosis, Survival Rate, fms-Like Tyrosine Kinase 3, Oncology, Drug Resistance, Neoplasm, Child, Preschool, Mutation, Cancer research, Female, Follow-Up Studies, Signal Transduction
Abstract: Constitutively activated FLT3 signaling is common in acute myeloid leukemia, and is currently under evaluation for targeted therapy, whereas little data is available in T-cell acute lymphoblastic leukemia (T-ALL). We analyzed 357 T-ALL cases for FLT3 mutations and transcript expression. FLT3 mutations (3% overall) and overexpression (FLT3 high expresser (FLT3(High))) were restricted to immature/TCRγδ T-ALLs. In vitro FLT3 inhibition induced apoptosis in only 30% of FLT3(High) T-ALLs and did not correlate with mutational status. In order to investigate the mechanisms of primary resistance to FLT3 inhibition, a broad quantitative screen for receptor kinome transcript deregulation was performed by Taqman Low Density Array. FLT3 deregulation was associated with overexpression of a network of receptor kinases (RKs), potentially responsible for redundancies and sporadic response to specific FLT3 inhibition. In keeping with this resistance to FLT3 inhibition could be reversed by dual inhibition of FLT3 and KIT with a synergistic effect. We conclude that immature T-ALL may benefit from multitargeted RK inhibition and that exploration of the receptor kinome defines a rational strategy for testing multitarget kinase inhibition in malignant diseases.
Published: 2012

34. An Early Thymic Precursor Phenotype Predicts Outcome Exclusively in HOXA-Overexpressing Adult T-ALL: A GRAALL Study

Author: Jean-François Hamel, Agata Cieslak, Norbert Ifrah, Laurent Sutton, Hervé Dombret, Salvatore Spicuglia, Vahid Asnafi, Amélie Trinquand, Jonathan Bond, Aurore Touzart, Isabelle Radford-Weiss, Elizabeth Macintyre, Tony Marchand, Institut Necker Enfants-Malades (INEM), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Microenvironnement et cancer (MiCa), Institut National de la Santé et de la Recherche Médicale (INSERM) - Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) - Université de Rennes 1 (UR1), Laboratoire d'hématologie, AP-HP Hôpital Necker - Enfants Malades [Paris] - Université Paris Descartes - Paris 5 (UPD5) - Assistance publique - Hôpitaux de Paris (AP-HP), Technologies avancées pour le génôme et la clinique (TAGC), Université de la Méditerranée - Aix-Marseille 2 - Aix Marseille Université (AMU) - Institut National de la Santé et de la Recherche Médicale (INSERM), Lymphocyte et cancer, IFR105 - Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) - Université Paris Diderot - Paris 7 (UPD7), Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) - Groupe Hospitalier Necker-Enfants Malades, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans [UNAM], Centre de recherche clinique, CHU Angers - Centre hospitalier Universitaire Angers, Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), CHU Angers - Hôtel-Dieu de Nantes - Hôpital Laennec - Faculté de Médecine d'Angers - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS) - CHU Nantes, Imagine - Institut des maladies génétiques (IHU), and Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - AP-HP Hôpital Necker - Enfants Malades [Paris]
Subjects: business.industry, medicine.medical_treatment, Immunology, Cell Biology, Hematology, Hematopoietic stem cell transplantation, medicine.disease, Biochemistry, Phenotype, [SDV] Life Sciences [q-bio], Immunophenotyping, Acute lymphocytic leukemia, medicine, Cancer research, business
Abstract: Introduction: Gene expression studies have consistently identified a HOXA positive (HOXAPos) subgroup of T-cell acute lymphoblastic leukemia (T-ALL) (Ferrando et al, Cancer Cell 2002, Soulier et al, Blood 2005, Homminga et al, Cancer Cell 2011). It is however unclear if HOXAPos T-ALL constitutes a distinct and homogeneous clinical entity, and the biological consequences of HOXA over-expression have not been systematically examined. Methods: We identified and characterized the biological characteristics and clinical outcome of 55 HOXAPos cases among a cohort of 209 adult T-ALL patients who were uniformly treated as part of the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003 and -2005 studies. Results: HOXAPos patients had higher rates of an early thymic precursor (ETP)-like immunophenotype (38% v 13.9%, p = 0.0008), early bone marrow chemoresistance (59.3% v 40.8%, p = 0.026) and positive minimal residual disease (MRD, 51.5% v 23.5%, p = 0.01) than the HOXANeg group. These differences were due to a particularly high frequency of chemoresistant ETP-ALL among HOXAPos cases harboring leukemic fusion proteins that trans-activate the HOXA locus (e.g. PICALM-MLLT10, SET-NUP214). Strikingly, the presence of an ETP-like immunophenotype conferred marked differences in outcome within the HOXAPos group (5 year event-free survival (EFS) 25% for HOXAPos ETP v 52.2% for HOXAPos non-ETP, p = 0.02), which were mirrored by corresponding increases in cumulative incidence of relapse (CIR, 57.1% v 25%, p = 0.01, Figure 1). In contrast, these survival differences were not seen in the HOXANeg patients, where ETP and non-ETP cases had similar 5 year EFS (54.9% v 50%, p = 0.73) and CIR (34.5% v 41.2%, p = 0.57). Multivariate analysis revealed that early bone marrow chemosensitivity was the clinico-biological covariate that had the strongest prognostic interaction with HOXA status. HOXA positivity conferred significant decreases in both the EFS and CIR of chemoresistant patients (p = 0.053 and 0.039 respectively), that was independent of white blood cell count (WCC), stem cell transplant (SCT), ETP phenotype, EGIL classification, and our recently reported risk classifier that integrates the prognostic effects of mutations of NOTCH1, FBXW7, RAS and PTEN (Trinquand et al, J Clin Oncol 2013). There were corresponding marked survival differences within the HOXAPos cohort between chemoresistant and chemosensitive cases. These disparities were not seen in the HOXANeg group, indicating that the prognostic value of chemosensitivity in adult T-ALL is specific to HOXAPos patients. Discussion: Our data show that clinico-biological phenotype is intimately linked to the underlying mechanism of HOXA locus deregulation, and we identify HOXA overexpression as a novel prognostic variable in ETP-ALL. Multivariate analysis suggests that this poor outcome is strongly related to intrinsic treatment resistance, and that this effect is exclusive to the HOXAPos cohort. Patients in the GRAALL-2003 and -2005 studies received enhanced induction and/ or salvage therapy in the event of poor early treatment response. Our results suggest that pediatric regimen-based intensification provides significant survival benefits for HOXANeg chemoresistant cases. In contrast, these modifications are inadequate for therapeutic rescue of the majority of HOXAPos chemoresistant ETP-ALL. The dramatically inferior prognosis of this group mandates consideration for alternative treatments in future clinical trials. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
Published: 2015

35. Oncogenic PTEN functions and models in T-cell malignancies

Author: Elizabeth Macintyre, Melania Tesio, Amélie Trinquand, and Vahid Asnafi
Subjects: 0301 basic medicine, Cancer Research, T cell, Biology, medicine.disease_cause, Lymphoma, T-Cell, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Molecular oncology, Genomic Instability, Malignant transformation, 03 medical and health sciences, Phosphatidylinositol 3-Kinases, Growth factor receptor, hemic and lymphatic diseases, Genetics, medicine, PTEN, Animals, Humans, Phosphorylation, Molecular Biology, PTEN Phosphohydrolase, Cell cycle, medicine.disease, Lymphoma, 030104 developmental biology, medicine.anatomical_structure, Cancer research, biology.protein, Carcinogenesis, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract: PTEN is a protein phosphatase that is crucial to prevent the malignant transformation of T-cells. Although a numerous mechanisms regulate its expression and function, they are often altered in T-cell acute lymphoblastic leukaemias and T-cell lymphomas. As such, PTEN inactivation frequently occurs in these malignancies, where it can be associated with chemotherapy resistance and poor prognosis. Different Pten knockout models recapitulated the development of T-cell leukaemia/lymphoma, demonstrating that PTEN loss is at the center of a complex oncogenic network that sustains and drives tumorigenesis via the activation of multiple signalling pathways. These aspects and their therapeutic implications are discussed in this review.
Published: 2015

36. Targeting IRAK1 in T-Cell acute lymphoblastic leukemia

Author: Hervé Dombret, Norbert Ifrah, Mathieu Simonin, Ludovic Lhermitte, Vahid Asnafi, Agata Cieslak, Mehdi Latiri, Amélie Trinquand, Elizabeth Macintyre, Patrick Villarese, Nawel Bedjaoui, Charles Dussiau, Els Verhoeyen, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Sorbonne Paris Cité (USPC), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe 'Contrôle Métabolique des Morts Cellulaires' (INSERM U1065 - C3M), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service des maladies du sang [CHU Angers], PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), This work was supported by grants to Necker laboratory from the 'Association Laurette Fugain', the 'Comité Départemental de la Ligue Contre le Cancer' and the Institut National du Cancer. Samples were collected and processed by the AP-HP 'Direction de Recherche Clinique' Tumor Bank at Necker-Enfants Malades. CD was supported by Assistance Publique des Hôpitaux de Paris (AP- HP)., Bernardo, Elizabeth, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, medicine.medical_specialty, T cell, medicine.medical_treatment, Lymphoblastic Leukemia, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, IRAK1, Targeted therapy, 03 medical and health sciences, Jurkat Cells, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Adrenal Cortex Hormones, Internal medicine, Cell Line, Tumor, medicine, Humans, Molecular Targeted Therapy, Receptor, 030304 developmental biology, Gynecology, 0303 health sciences, Hematology, Kinase, business.industry, Cell Cycle, therapeutic target, Cell cycle, 3. Good health, medicine.anatomical_structure, Interleukin-1 Receptor-Associated Kinases, kinases, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Gene Knockdown Techniques, Immunology, Female, business, T-ALL, Signal Transduction, Research Paper
Abstract: // Charles Dussiau 1, * , Amelie Trinquand 1, * , Ludovic Lhermitte 1 , Mehdi Latiri 1 , Mathieu Simonin 1 , Agata Cieslak 1 , Nawel Bedjaoui 1 , Patrick Villarese 1 , Els Verhoeyen 2, 3 , Herve Dombret 4 , Norbert Ifrah 5 , Elizabeth Macintyre 1 , Vahid Asnafi 1 1 Universite Paris Descartes Sorbonne Cite, Institut Necker-Enfants Malades (INEM), Institut National de Recherche Medicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hopitaux de Paris (AP-HP), Hopital Necker-Enfants Malades, Paris, France 2 CIRI, EVIR Team, INSERM, U1111, CNRS, UMR5308, Universite de Lyon-1, ENS de Lyon, Lyon, France 3 INSERM, U1065, C3M, Equipe “Controle Metabolique des Morts Cellulaires”, Nice, France 4 University Paris 7, Hopital Saint-Louis, AP-HP, Department of Hematology and Institut Universitaire d’Hematologie, EA, Paris, France 5 PRES LUNAM, CHU Angers Service des Maladies du Sang et INSERM U 892, Angers, France * These authors have contributed equally to this work Correspondence to: Vahid Asnafi, e-mail: vahid.asnafi@nck.aphp.fr Keywords: T-ALL, IRAK1, kinases, therapeutic target Received: December 12, 2014 Accepted: May 20, 2015 Published: June 01, 2015 ABSTRACT T-cell acute lymphoblastic leukemia (T-ALL) represents expansion of cells arrested at specific stages of thymic development with the underlying genetic abnormality often determining the stage of maturation arrest. Although their outcome has been improved with current therapy, survival rates remain only around 50% at 5 years and patients may therefore benefit from specific targeted therapy. Interleukin receptor associated kinase 1 (IRAK1) is a ubiquitously expressed serine/threonine kinase that mediates signaling downstream to Toll-like (TLR) and Interleukin-1 Receptors (IL1R). Our data demonstrated that IRAK1 is overexpressed in all subtypes of T-ALL, compared to normal human thymic subpopulations, and is functional in T-ALL cell lines. Genetic knock-down of IRAK1 led to apoptosis, cell cycle disruption, diminished proliferation and reversal of corticosteroid resistance in T-ALL cell lines. However, pharmacological inhibition of IRAK1 using a small molecule inhibitor (IRAK1/4-Inh) only partially reproduced the results of the genetic knock-down. Altogether, our data suggest that IRAK1 is a candidate therapeutic target in T-ALL and highlight the requirement of next generation IRAK1 inhibitors.
Published: 2015

37. RUNX1-dependent RAG1 deposition instigates human TCR-δ locus rearrangement

Author: Don-Marc Franchini, Emmanuelle Six, Els Verhoeyen, Ludovic Lhermitte, Isabelle André-Schmutz, Vahid Asnafi, Stéphanie Gon, Dominique Payet-Bornet, Laurent Vanhille, Jérôme Larghero, Christian Reimann, Sandrine Le Noir, Salvatore Spicuglia, Agata Cieslak, Bertrand Nadel, Jonathan Bond, Amélie Trinquand, Elizabeth Macintyre, Anton W. Langerak, Mathieu Simonin, Patrick Villarese, CHU Necker - Enfants Malades [AP-HP], Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Technologies avancées pour le génôme et la clinique ( TAGC ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Cellular differentiation, [SDV]Life Sciences [q-bio], Gene Rearrangement, delta-Chain T-Cell Antigen Receptor, Molecular Sequence Data, Immunology, Locus (genetics), chemical and pharmacologic phenomena, Biology, Article, Recombination-activating gene, Cell Line, Mice, 03 medical and health sciences, 0302 clinical medicine, Species Specificity, T-Lymphocyte Subsets, hemic and lymphatic diseases, Recombinase, Animals, Humans, Immunology and Allergy, Lymphopoiesis, Binding site, VDJ Recombinases, 030304 developmental biology, Homeodomain Proteins, 0303 health sciences, Binding Sites, Base Sequence, [ SDV ] Life Sciences [q-bio], T-cell receptor, Correction, Cell Differentiation, hemic and immune systems, DNA, Molecular biology, Chromatin, Kinetics, HEK293 Cells, embryonic structures, Core Binding Factor Alpha 2 Subunit, 030215 immunology
Abstract: Within the human TCR-α/δ locus, ordered rearrangements requires RUNX1, which binds to the Dδ2-23RSS and interacts with RAG1 to enhance RAG1 deposition at this site. Absence of this RUNX1 binding site in the homologous murine Dδ1-23RSS offers an explanation for the lack of ordered TCR-δ gene assembly in mice., V(D)J recombination of TCR loci is regulated by chromatin accessibility to RAG1/2 proteins, rendering RAG1/2 targeting a potentially important regulator of lymphoid differentiation. We show that within the human TCR-α/δ locus, Dδ2-Dδ3 rearrangements occur at a very immature thymic, CD34+/CD1a−/CD7+dim stage, before Dδ2(Dδ3)-Jδ1 rearrangements. These strictly ordered rearrangements are regulated by mechanisms acting beyond chromatin accessibility. Importantly, direct Dδ2-Jδ1 rearrangements are prohibited by a B12/23 restriction and ordered human TCR-δ gene assembly requires RUNX1 protein, which binds to the Dδ2-23RSS, interacts with RAG1, and enhances RAG1 deposition at this site. This RUNX1-mediated V(D)J recombinase targeting imposes the use of two Dδ gene segments in human TCR-δ chains. Absence of this RUNX1 binding site in the homologous mouse Dδ1-23RSS provides a molecular explanation for the lack of ordered TCR-δ gene assembly in mice and may underlie differences in early lymphoid differentiation between these species.
Published: 2014

38. BRAF(V600E) mutation in a histiocytic sarcoma arising from hairy cell leukemia

Author: Marie-Odile North, Richard Delarue, Jean-François Emile, Amélie Trinquand, Nicole Brousse, Bruno Varet, Sophie Kaltenbach, Olivier Hermine, Chantal Brouzes, Laure Gibault, David Michonneau, and Coralie Derrieux
Subjects: Male, Proto-Oncogene Proteins B-raf, Cancer Research, Antineoplastic Agents, Histiocytic sarcoma, Flow cytometry, Remission induction, Recurrence, medicine, Humans, Hairy cell leukemia, Aged, Cell Proliferation, Leukemia, Hairy Cell, medicine.diagnostic_test, business.industry, Cell growth, Remission Induction, medicine.disease, Flow Cytometry, Leukemia, Oncology, Mutation (genetic algorithm), Mutation, Cancer research, Cladribine, Histiocytic Sarcoma, business
Published: 2014

39. Oncogenetic Risk Classification Based on NOTCH1/FBXW7/RAS/PTEN Mutation Profiles Improves Outcome Prediction in Pediatric T-Cell Acute Lymphoblastic Leukemia, Treated According the Fralle 2000 T Guidelines

Author: Arnaud Petit, Elizabeth Macintyre, Guy Leverger, Gérard Michel, Amélie Trinquand, Sylvie Chevret, Paola Ballerini, Benoit Brethon, Jean Soulier, Jean-Michel Cayuela, André Baruchel, Hélène Lapillonne, Claire Berger, Judith Landman-Parker, Nathalie Grardel, Aurore Touzart, Claude Preudhomme, Vahid Asnafi, and Pascal Chastagner
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Pediatrics, Lymphoblastic Leukemia, T cell, Immunology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, PTEN, biology, business.industry, Cell Biology, Hematology, Minimal residual disease, Biological materials, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cohort, biology.protein, Risk classification, Outcome prediction, business
Abstract: Background: Risk stratification in childhood T-cell acute lymphoblastic leukemia (T-ALL) is crucial to drive treatment decisions. Since patients with induction failure or relapse are often refractory to further treatment, identifying high risk patients up-front will allow improved treatment. While minimal residual disease (MRD) is the strongest prognosis risk factor used after complete remission (CR), NOTCH1/FBXW7 (N/F) and RAS/PTEN (R/P) mutation profiles at diagnosis have recently been identified to predict outcome in adult T-ALL. Objective: to test whether an oncogenetic classifier using N/F and R/P mutations could improve the detection of children with T-ALL at risk of relapse. Methods: 405 patients with T-ALL aged from 1 to 14 years were treated according to FRALLE T guidelines (FRALLE Study group) between 2000 and 2010. Among them, 220 patients, for whom biological material at diagnosis was available, were tested retrospectively for N/F and R/P mutations. These study cohort patients were representative of overall FRALLE 2000 T-ALLs. CR was achieved in 213 patients. MRD (IgH-TCR markers) tested at CR (day 35) was available for 191 patients. MRD was Results: 111 patients were classified as LoR and 109 as HiR. Five-year-CIR and DFS were respectively 35.5% (95% CI, 26.7-44.3) and 59% (95%CI, 50.2-69.6) for HiR versus 13% (95% CI, 6.8-19.2) and 86.8% (80.5-93.5) for the LoR group (Figures A and B). HiR patients were significantly associated with MRD ≥ 10-4 (p=0.0004) and higher risk of relapse (p=0.00002). Among patients with MRD ≥ 10-4, HiR feature worsened the risk of relapse: 5-year-CIR and DFS were respectively 42.8% (95% CI, 28.9-56.7) and 71.1% (95%CI, 56.0-90.2) in HiR versus 28.9% (95% CI, 11.7-46.1) and 50.9% (95%CI, 38.4-67.6) in the LoR group. Among patients with MRD 10-4, demonstrated an increasing CIR, up to 45.8% if all three were associated. Conclusion: in childhood T-ALL, oncogenetic classification using N/F and R/P mutation profiles is an independent predictor of relapse. When combined with MRD and WBC count ≥200 G/L, it significantly improved relapse prediction, particularly amongst the 60% of T-ALLs with MRD Figure Figure. Disclosures No relevant conflicts of interest to declare.
Published: 2016

40. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study

Author: Raouf Ben Abdelali, Véronique Lhéritier, Jean-Yves Cahn, Françoise Huguet, Norbert Ifrah, Agnès Buzyn, Noémie de Gunzburg, Elizabeth Macintyre, Vahid Asnafi, Dominique Payet-Bornet, Sébastien Maury, Jonathan Bond, Thibaud Leguay, Amélie Trinquand, Bertrand Nadel, André Delannoy, Kheira Beldjord, Hervé Dombret, Xavier Thomas, Jérôme Lambert, Ludovic Lhermitte, Hossein Mossafa, Etienne Lengliné, Yves Chalandon, Caroline Bonmati, Aline Tanguy-Schmidt, Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Cytogénétique - Pasteur-Cerba, Laboratoire Pasteur-Cerba, Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), TheREx, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ), Hôpital de Jolimont, Haine-Saint-Paul and Cliniques Universitaires St Luc, Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service d'hématologie clinique [Avicenne], Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Lymphocyte et cancer, IFR105-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], IFR105-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Université Toulouse III - Paul Sabatier (UT3), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre de Recherche en Cancérologie de Lyon (CRCL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Avicenne, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Ras Proteins/genetics, Oncology, Pathology, MESH : F-Box Proteins, DNA Mutational Analysis, Cell Cycle Proteins, MESH : Gene Deletion, MESH: Receptor, Notch1, 0302 clinical medicine, MESH : Cell Cycle Proteins, Receptor, Notch1, MESH: DNA Mutational Analysis, Young adult, ddc:616, 0303 health sciences, Hazard ratio, PTEN Phosphohydrolase/genetics, hemic and immune systems, 3. Good health, MESH : Phenotype, MESH: Young Adult, 030220 oncology & carcinogenesis, Predictive value of tests, Cohort, F-Box Proteins/genetics, MESH : Proto-Oncogene Proteins, MESH: Membrane Proteins, MESH: ras Proteins, medicine.medical_specialty, MESH : Young Adult, MESH : DNA Mutational Analysis, MESH: Phenotype, MESH: PTEN Phosphohydrolase, Disease-Free Survival, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, MESH: Cell Cycle Proteins, Humans, PTEN, Ubiquitin-Protein Ligases/genetics, MESH : Predictive Value of Tests, MESH: Kaplan-Meier Estimate, Cell Cycle Proteins/genetics, Receptor, Notch1/genetics, [ SDV.IMM.II ] Life Sciences [q-bio]/Immunology/Innate immunity, MESH: Humans, Proportional hazards model, F-Box Proteins, MESH : Humans, MESH: Adult, MESH : Proportional Hazards Models, MESH: Ubiquitin-Protein Ligases, MESH : Membrane Proteins, MESH: Disease-Free Survival, Mutation, ras Proteins, Adult Acute Lymphoblastic Leukemia, MESH : Genetic Predisposition to Disease, MESH : Ubiquitin-Protein Ligases, MESH : GTP Phosphohydrolases, MESH: Female, Gene Deletion, Cancer Research, F-Box-WD Repeat-Containing Protein 7, Time Factors, MESH : Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Kaplan-Meier Estimate, MESH : PTEN Phosphohydrolase, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, GTP Phosphohydrolases, MESH: Proportional Hazards Models, MESH: Risk Factors, Risk Factors, hemic and lymphatic diseases, MESH : Female, biology, MESH : Receptor, Notch1, MESH: Genetic Predisposition to Disease, MESH : Adult, MESH : Risk Factors, MESH: Predictive Value of Tests, MESH: Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Phenotype, MESH : Disease-Free Survival, Female, MESH : Mutation, MESH : Time Factors, Adult, MESH: Mutation, MESH: GTP Phosphohydrolases, Ubiquitin-Protein Ligases, MESH : Male, MESH: F-Box Proteins, MESH: Multivariate Analysis, MESH : Kaplan-Meier Estimate, Young Adult, Predictive Value of Tests, Proto-Oncogene Proteins, Internal medicine, medicine, Genetic Predisposition to Disease, Membrane Proteins/genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/classification/genetics/mortality/therapy, Proportional Hazards Models, 030304 developmental biology, business.industry, MESH: Time Factors, PTEN Phosphohydrolase, Membrane Proteins, MESH : Multivariate Analysis, GTP Phosphohydrolases/genetics, MESH: Male, MESH: Proto-Oncogene Proteins, Proto-Oncogene Proteins/genetics, MESH: Gene Deletion, Multivariate Analysis, biology.protein, MESH : ras Proteins, business
Abstract: Purpose The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse. Patients and Methods In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion). Results N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001). Conclusion These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.
Published: 2013

41. Successful Salvage Therapy By Idelalisib Followed By Haploidentical Allogenic Transplantation of an Alemtuzumab-Refractory T-Cell Prolymphocytic Leukemia

Author: Olivier Tournilhac, Ludovic Lhermitte, Laurent Frenzel, Julien Lenglet, Amélie Trinquand, Ali Bazarbachi, and Olivier Hermine
Subjects: Oncology, medicine.medical_specialty, education.field_of_study, business.industry, Immunology, Population, Salvage therapy, Cell Biology, Hematology, medicine.disease, Biochemistry, Transplantation, medicine.anatomical_structure, Internal medicine, medicine, Alemtuzumab, T-cell prolymphocytic leukemia, Bone marrow, CD5, education, business, Idelalisib, medicine.drug
Abstract: Background T-cell prolymphocytic leukemia (T-PLL) is a rare disease of extremely poor outcome. The current standard of care involves intravenous Alemtuzumab with high response rates. Virtually all patients experience relapse and the 5-years overall survival is not higher than 5%. Allogenic bone marrow transplantation is the only curative option. Case presentation A 35 years-old male was diagnosed with T-PLL in early 2014 with skin infiltration, fatigue, hepatomegaly, splenomegaly (28 cm), and lymphadenopathies. Immunophenotypic features of circulating lymphocytes showed a T-cell lymphoproliferation (CD2+ CD3+ CD5+ CD7+ CD8+). TCL1 hyperexpression was assessed on bone marrow and lymph node biopsy samples. There was a rearrangement of chromosome 14 involving TCL1 on circulating cells. Pentostatin was initiated for 2 cycles without success. IV alemtuzumab (30mg/m2) was then introduced. After 8 weekly cycles, a CT scan showed a reduction of the splenomegaly (22 cm), a stable hepatomegaly, and no remaining lymphadenopathy. No abnormal circulating lymphocytes were detectable. After 14 cycles, the patient showed cervical painful lymph nodes. A needle aspiration revealed relapse with T-PLL cells. We then introduced idelalisib (150 mg, twice daily). Alemtuzumab was discontinued. One week after the introduction of idelalisib, physical examination revealed the disappearance of all peripheral lymph nodes. After 2 weeks, the spleen size was reduced to 16 cm and a body PET-CT was negative, proving metabolic remission. No circulating lymphocyte could be found. The patient was considered as being in complete remission (CR) and underwent haplo-identical transplantation. Idelalisib was discontinued after three weeks of exposure before transplantation and reintroduced from days 30 to 60. At day 100 after transplantation, the patient was in persistent CR: a peripheral immunophenotypic study was performed, no clonal T population was found, chimerism was 100% of donor origin. A bone marrow aspirate was quantitatively and qualitatively normal. Seven months after transplant, the patient remains in CR with a grade 1 skin chronic GVHD. Biological rationale Idealisib is a delta isoform inhibitor of protein phosphatidylinositol 3 kinase (PI3K). TCL1 is an overexpressed oncoprotein described in the majority of T-PLL due to chromosomal 14 rearrangement. TCL1 modulates AKT activity, facilitating both AKT dimerization and phosphorylation upon PI3K stimulation. The PI3K produces PIP2 and PIP3, which are required to phosphorylate AKT. Even if TCL1 is not sufficient to transform T cells into T-PLL cells and requires secondary genetic events as suggested in murine models, AKT hyperactivation may participate in T-cell proliferation (through the GSK-3β and mTOR pathways), and survival (through the NFκB pathway). We hypothesized that the inhibition of the PI3K with idelalisib would inhibit growth and eventually cell survival of the T-PLL cell, depending on the secondary genetic events. In order to support this hypothesis, we investigated the biochemical and functional effects of idelalisib in vitro. Fresh primary T-PLL cells were obtained from the ascites of an another case of T-PLL (CD2+, CD3+, CD5+, CD7+, CD4/CD8+, complex caryotype involving chromosome 14). In vitro exposure of primary T-PLL cells to idelalisib led to a dramatic and dose-dependent decrease in AKT phosphorylation after 24 hours (figure 1) and ex vivo after 5 days (figure 2). However, no apoptotic response was observed, neither in vitro nor ex vivo, even though therapeutic levels of idelalisib were reached in the ascites. Conclusion We report the first case of idealisib successfully used as a salvage therapy in T-PLL, leading to complete remission. It was used as a bridge to transplantation for a patient who is still in complete remission 7 months after transplantation. Our results provide a paradigm for the use of a PI3K inhibitor in T-PLL, which results in AKT dephosphorylation. The lack of functional response for the second patient suggests that the clinical response may depend on other oncogenic events, which could bypass AKT dependency. There is a need to identify a patient subgroup that may benefit from PI3K inhibition. In an attempt to identify molecular mechanisms underlying this resistance, comparative full exome sequencing is being performed for both patients and will be shown at the meeting. Disclosures Off Label Use: idelalisib, PI3-Kinase inhibitor. Tournilhac:Roche: Other: Travel support, Research Funding; Celgene: Other: Travel support; Mundiphrama: Honoraria, Other: Travel Support, Research Funding; GSK: Other: Travel Support, Research Funding; Janssen Cilag: Honoraria, Other: Travel support; Gilead: Other: Travel Funding.
Published: 2015

42. Towards a Purely Oncogenetic Risk Classification of Adult T-ALL: a GRAALL Study

Author: Noémie de Gunzburg, Thibaut Leguay, Dominique Payet-Bornet, Aline Tanguy-Schmidt, Véronique Lhéritier, Elizabeth Macintyre, Vahid Asnafi, Agnès Buzyn, Raouf Ben Abdelali, Sébastien Maury, Jérôme Lambert, Norbert Ifrah, Jean-Yves Cahn, Françoise Huguet, Xavier Thomas, Bertrand Nadel, Amélie Trinquand, André Delannoy, Hossein Mossafa, Hervé Dombret, Caroline Bonmati, Ludovic Lhermitte, Etienne Lengliné, and Yves Chalandon
Subjects: Oncology, Mutation, medicine.medical_specialty, biology, Proportional hazards model, Immunology, Hazard ratio, Cell Biology, Hematology, medicine.disease_cause, Bioinformatics, Biochemistry, Phenotype, Exon, Internal medicine, biology.protein, medicine, PTEN, Good prognosis, Risk classification
Abstract: Abstract 881 T-cell acute lymphoblastic leukemia (T-ALL) represents a heterogeneous group of acute leukemias, which account for 25% of adult ALL. The GRAALL group recently reported a significant improvement in the outcome of BCR-ABL negative adult ALL using an intensified treatment protocol and a significantly better outcome in T-ALL harbouring NOTCH1 and/or FBXW7 (N/F) mutations compared to unmutated cases. Despite this, a third of N/F mutated T-ALL patients relapse and the identification of a T-ALL subgroup with very favorable outcome remains desirable. In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and 2005 trials, we searched for N/K-RAS (exon 1) mutations and PTEN (exon 7 mutations and gene deletion by CGH-array SNP-6 Affymetrix®) defects, which are considered as “type B3” mutations involved in pre-TCR signalling. Overall survival (OS) and event-free survival (EFS) were estimated by the Kaplan-Meier method, and then compared by the log-rank test. NOTCH1 and/or FBXW7 mutations were identified in 143 (67%) of the 212 patients and lack of N/F mutation was associated with a poor prognostic. N-RAS, K-RAS and PTEN mutations were identified in 3/191 (1.6%), 17/191 (8.9%) and 17/175 (9.7%) patients, respectively. PTEN genomic deletions/mutations and N/K-RAS activating mutations were virtually mutually exclusive. N/K-RAS mutations were more frequent in TCR negative phenotype and CNS positive T-ALLs, but did not correlate with other classical parameters, EGIL phenotype, N/F status, or cortico- or chemo-sensitivity. PTEN alterations were more frequent in mature TCR expressing, SIL-TAL+, N/F unmutated cases with high leukemic bulk tumors, but did not significantly differed with respect to age, gender, CNS involvement, cortico- or chemo-sensitivity. When analyzed separately, N/K-RAS mutations or PTEN genomic abnormalities demonstrated trends to a worse outcome. We then analyzed the effect of N/K-RAS mutations and/or PTEN genomic abnormalities on the good prognosis associated with N/F mutations by a multivariate Cox model for EFS and OS, entering the two N/F and RAS/PTEN covariates, as well as an interaction term. The prognostic significance of N/F mutations was still observed (HR, 0.26 [95% CI, 0.15–0.46] and 0.26 [95% CI, 0.14–0.49] with P Taken together, these data demonstrate that detection of RAS and PTEN mutations add significant prognostic value to assessment of N/F status, allowing identification of nearly 50% very good prognosis T-ALL adults. Figure 1A Figure 1A. Figure 1B Figure 1B. Disclosures: No relevant conflicts of interest to declare.

43. NKP46 EXPRESSION IS A DIAGNOSTIC AND PROGNOSTIC BIOMARKER IN PRIMARY GASTROINTESTINAL T-CELL LYMPHOPROLIFERATIONS. A CELAC NETWORK STUDY

Author: Bertrand Meresse, Elizabeth Macintyre, Ambroise Marçais, Georgia Malamut, Morgane Cheminant, Felipe Suarez, Laurent Frenzel, Amélie Trinquand, F. Lhospice, Nicole Brousse, Nicolas Guegan, Christophe Cellier, Olivier Hermine, Julie Bruneau, C. Bonnafous, Richard Delarue, David Sibon, Vahid Asnafi, Nadine Cerf-Bensussan, Thierry Jo Molina, and Ludovic Lhermitte
Subjects: 0301 basic medicine, Cancer Research, Primary (chemistry), business.industry, T cell, Hematology, General Medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Oncology, Cancer research, Medicine, 030211 gastroenterology & hepatology, Prognostic biomarker, business

44. Early Response-Based Therapy Stratification Improves Survival in Adult Early Thymic Precursor Acute Lymphoblastic Leukemia: A Group for Research on Adult Acute Lymphoblastic Leukemia Study.

Author: Bond J, Graux C, Lhermitte L, Lara D, Cluzeau T, Leguay T, Cieslak A, Trinquand A, Pastoret C, Belhocine M, Spicuglia S, Lheritier V, Leprêtre S, Thomas X, Huguet F, Ifrah N, Dombret H, Macintyre E, Boissel N, and Asnafi V
Subjects: Adult, Cyclophosphamide administration & dosage, DNA Methylation genetics, DNA Mutational Analysis, Drug Resistance, Neoplasm, Female, Genotype, Hematopoiesis genetics, Histones chemistry, Humans, Immunophenotyping, Male, Prognosis, Receptors, Cytokine genetics, Signal Transduction genetics, Survival Rate, Transplantation, Homologous, ras Proteins genetics, ras Proteins metabolism, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Hematopoietic Stem Cell Transplantation, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma therapy, Thymus Neoplasms genetics, Thymus Neoplasms therapy
Abstract: Purpose Early thymic precursor (ETP) acute lymphoblastic leukemia (ALL) is an immunophenotypically defined subgroup of T-cell ALL (T-ALL) associated with high rates of intrinsic treatment resistance. Studies in children have shown that the negative prognostic impact of chemotherapy resistance is abrogated by the implementation of early response-based intensification strategies. Comparable data in adults are lacking. Patients and Methods We performed comprehensive clinicobiologic, genetic, and survival analyses of a large cohort of 213 adult patients with T-ALL, including 47 patients with ETP-ALL, treated in the GRAALL (Group for Research on Adult Acute Lymphoblastic Leukemia) -2003 and -2005 studies. Results Targeted next-generation sequencing revealed that the genotype of immunophenotypically defined adult T-ALL is similar to the pediatric equivalent, with high rates of mutations in factors involved in cytokine receptor and RAS signaling (62.2%), hematopoietic development (29.7%), and chemical modification of histones (48.6%). In contrast to pediatric cases, mutations in DNA methylation factor genes were also common (32.4%). We found that despite expected high levels of early bone marrow chemotherapy resistance (87%), the overall prognosis for adults with ETP-ALL treated using the GRAALL protocols was not inferior to that of the non-ETP-ALL group (5-year overall survival: ETP, 59.6%; 95% CI, 44.2% to 72.0% v non-ETP, 66.5%; 95% CI, 58.7% to 73.2%; P = 0.33) and that allogeneic stem-cell transplantation had a beneficial effect in a large proportion of patients with ETP-ALL. Conclusion Our results suggest that the use of response-based risk stratification and therapy intensification abrogates the poor prognosis of adult ETP-ALL.
Published: 2017
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45. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study.

Author: Trinquand A, Tanguy-Schmidt A, Ben Abdelali R, Lambert J, Beldjord K, Lengliné E, De Gunzburg N, Payet-Bornet D, Lhermitte L, Mossafa H, Lhéritier V, Bond J, Huguet F, Buzyn A, Leguay T, Cahn JY, Thomas X, Chalandon Y, Delannoy A, Bonmati C, Maury S, Nadel B, Macintyre E, Ifrah N, Dombret H, and Asnafi V
Subjects: Adult, Disease-Free Survival, F-Box-WD Repeat-Containing Protein 7, Female, Genetic Predisposition to Disease, Humans, Kaplan-Meier Estimate, Male, Multivariate Analysis, Phenotype, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma classification, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma mortality, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma therapy, Predictive Value of Tests, Proportional Hazards Models, Proto-Oncogene Proteins p21(ras), Risk Factors, Time Factors, Young Adult, Cell Cycle Proteins genetics, DNA Mutational Analysis, F-Box Proteins genetics, GTP Phosphohydrolases genetics, Gene Deletion, Membrane Proteins genetics, Mutation, PTEN Phosphohydrolase genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Proto-Oncogene Proteins genetics, Receptor, Notch1 genetics, Ubiquitin-Protein Ligases genetics, ras Proteins genetics
Abstract: Purpose: The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse., Patients and Methods: In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion)., Results: N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001)., Conclusion: These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.
Published: 2013
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