Search

Your search keyword '"Nathalie Grardel"' showing total 26 results
Start Over Author "Nathalie Grardel" Language english
26 results on '"Nathalie Grardel"'

1. Clinico-biological features of T-cell acute lymphoblastic leukemia with fusion proteins

Author

Thomas Steimlé, Marie-Emilie Dourthe, Marion Alcantara, Aurore Touzart, Mathieu Simonin, Johanna Mondesir, Ludovic Lhermitte, Jonathan Bond, Carlos Graux, Nathalie Grardel, Jean-Michel Cayuela, Isabelle Arnoux, Virginie Gandemer, Marie Balsat, Norbert Vey, Elizabeth Macintyre, Norbert Ifrah, Hervé Dombret, Arnaud Petit, André Baruchel, Philippe Ruminy, Nicolas Boissel, and Vahid Asnafi

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract T-cell acute lymphoblastic leukemias (T-ALL) represent 15% of pediatric and 25% of adult ALL. Since they have a particularly poor outcome in relapsed/refractory cases, identifying prognosis factors at diagnosis is crucial to adapting treatment for high-risk patients. Unlike acute myeloid leukemia and BCP ALL, chromosomal rearrangements leading to chimeric fusion-proteins with strong prognosis impact are sparsely reported in T-ALL. To address this issue an RT-MPLA assay was applied to a consecutive series of 522 adult and pediatric T-ALLs and identified a fusion transcript in 20% of cases. PICALM-MLLT10 (4%, n = 23), NUP214-ABL1 (3%, n = 19) and SET-NUP214 (3%, n = 18) were the most frequent. The clinico-biological characteristics linked to fusion transcripts in a subset of 235 patients (138 adults in the GRAALL2003/05 trials and 97 children from the FRALLE2000 trial) were analyzed to identify their prognosis impact. Patients with HOXA trans-deregulated T-ALLs with MLLT10, KMT2A and SET fusion transcripts (17%, 39/235) had a worse prognosis with a 5-year EFS of 35.7% vs 63.7% (HR = 1.63; p = 0.04) and a trend for a higher cumulative incidence of relapse (5-year CIR = 45.7% vs 25.2%, HR = 1.6; p = 0.11). Fusion transcripts status in T-ALL can be robustly identified by RT-MLPA, facilitating risk adapted treatment strategies for high-risk patients.

Published
2022
Full Text
View/download PDF

2. Oncogenetic landscape and clinical impact of IDH1 and IDH2 mutations in T-ALL

Author

Mathieu Simonin, Aline Schmidt, Christophe Bontoux, Marie-Émilie Dourthe, Etienne Lengliné, Guillaume P. Andrieu, Ludovic Lhermitte, Carlos Graux, Nathalie Grardel, Jean-Michel Cayuela, Françoise Huguet, Isabelle Arnoux, Stéphane Ducassou, Elizabeth Macintyre, Virginie Gandemer, Hervé Dombret, Arnaud Petit, Norbert Ifrah, André Baruchel, Nicolas Boissel, and Vahid Asnafi

Subjects
IDH1, IDH2, T-ALL, Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract IDH1 and IDH2 mutations (IDH1/2 Mut ) are recognized as recurrent genetic alterations in acute myeloid leukemia (AML) and associated with both clinical impact and therapeutic opportunity due to the recent development of specific IDH1/2 Mut inhibitors. In T-cell acute lymphoblastic leukemia (T-ALL), their incidence and prognostic implications remain poorly reported. Our targeted next-generation sequencing approach allowed comprehensive assessment of genotype across the entire IDH1 and IDH2 locus in 1085 consecutive unselected and newly diagnosed patients with T-ALL and identified 4% of, virtually exclusive (47 of 49 patients), IDH1/2 Mut. Mutational patterns of IDH1/2 Mut in T-ALL present some specific features compared to AML. Whereas IDH2 R140Q mutation was frequent in T-ALL (25 of 51 mutations), the IDH2 R172 AML hotspot was absent. IDH2 mutations were associated with older age, an immature phenotype, more frequent RAS gain-of-function mutations and epigenetic regulator loss-of-function alterations (DNMT3A and TET2). IDH2 mutations, contrary to IDH1 mutations, appeared to be an independent prognostic factor in multivariate analysis with the NOTCH1/FBXW7/RAS/PTEN classifier. IDH2 Mut were significantly associated with a high cumulative incidence of relapse and very dismal outcome, suggesting that IDH2-mutated T-ALL cases should be identified at diagnosis in order to benefit from therapeutic intensification and/or specific IDH2 inhibitors.

Published
2021
Full Text
View/download PDF

3. Clinical and biological features of PTPN2-deleted adult and pediatric T-cell acute lymphoblastic leukemia

Author

Marion Alcantara, Mathieu Simonin, Ludovic Lhermitte, Aurore Touzart, Marie Emilie Dourthe, Mehdi Latiri, Nathalie Grardel, Jean Michel Cayuela, Yves Chalandon, Carlos Graux, Hervé Dombret, Norbert Ifrah, Arnaud Petit, Elizabeth Macintyre, André Baruchel, Nicolas Boissel, and Vahid Asnafi

Subjects
Specialties of internal medicine, RC581-951
Abstract

Abstract: Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a phosphatase known to be a tumor suppressor gene in T-cell acute lymphoblastic leukemia (T-ALL). Because the full clinicobiologic characteristics of PTPN2 loss remain poorly reported, we aimed to provide a comprehensive analysis of PTPN2 deletions within a cohort of 430 patients, including 216 adults and 214 children treated according to the GRAALL03/05 (#NCT00222027 and #NCT00327678) and the FRALLE2000 protocols, respectively. We used multiplex ligation-dependent probe amplification to identify an 8% incidence of PTPN2 deletion, which was comparable in adult (9%) and pediatric (6%) populations. PTPN2 deletions were significantly associated with an αβ lineage and TLX1 deregulation. Analysis of the mutational genotype of adult T-ALL revealed a positive correlation between PTPN2 deletions and gain-of-function alterations in the IL7R/JAK-STAT signaling pathway as well as PHF6 and WT1 mutations. Of note, PTPN2 and PTEN (phosphatase and tensin homolog) deletions were mutually exclusive. Regarding treatment response, PTPN2-deleted T-ALLs were associated with a higher glucocorticoid response and a trend for improved survival in children, but not in adults, with a 5-year cumulative incidence of relapse of 8% for PTPN2-deleted pediatric cases vs 26% (P = .177).

Published
2019
Full Text
View/download PDF

4. Efficacy of Tyrosine Kinase Inhibitor Therapy in a Chemotherapy-refractory B-cell Precursor Acute Lymphoblastic Leukemia With ZC3HAV1-ABL2 Fusion

Author

Gauthier Decool, Carine Domenech, Nathalie Grardel, Adriana Plesa, Imelda Raczkiewicz, Benoit Ducourneau, Philippe Ruminy, Marie-Pierre Pages, Sandrine Girard, Laurène Fenwarth, Claude Preudhomme, Yves Bertrand, and Nicolas Duployez

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2019
Full Text
View/download PDF

6. CD200/BTLA deletions in pediatric precursor B-cell acute lymphoblastic leukemia treated according to the EORTC-CLG 58951 protocol

Author

Farzaneh Ghazavi, Emmanuelle Clappier, Tim Lammens, Stefan Suciu, Aurélie Caye, Samira Zegrari, Marleen Bakkus, Nathalie Grardel, Yves Benoit, Yves Bertrand, Odile Minckes, Vitor Costa, Alina Ferster, Françoise Mazingue, Geneviève Plat, Emmanuel Plouvier, Marilyne Poirée, Anne Uyttebroeck, Jutte van der Werff-ten Bosch, Karima Yakouben, Hetty Helsmoortel, Magali Meul, Nadine Van Roy, Jan Philippé, Frank Speleman, Hélène Cavé, Pieter Van Vlierberghe, and Barbara De Moerloose

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

DNA copy number analysis has been instrumental for the identification of genetic alterations in B-cell precursor acute lymphoblastic leukemia. Notably, some of these genetic defects have been associated with poor treatment outcome and might be relevant for future risk stratification. In this study, we characterized recurrent deletions of CD200 and BTLA genes, mediated by recombination-activating genes, and used breakpoint-specific polymerase chain reaction assay to screen a cohort of 1154 cases of B-cell precursor acute lymphoblastic leukemia uniformly treated according to the EORTC-CLG 58951 protocol. CD200/BTLA deletions were identified in 56 of the patients (4.8%) and were associated with an inferior 8-year event free survival in this treatment protocol [70.2% ± 1.2% for patients with deletions versus 83.5% ± 6.4% for non-deleted cases (hazard ratio 2.02; 95% confidence interval 1.23–3.32; P=0.005)]. Genetically, CD200/BTLA deletions were strongly associated with ETV6-RUNX1-positive leukemias (P

Published
2015
Full Text
View/download PDF

7. CD3−CD4+ lymphoid variant of hypereosinophilic syndrome: nodal and extranodal histopathological and immunophenotypic features of a peripheral indolent clonal T-cell lymphoproliferative disorder

Author

Guillaume Lefèvre, Marie-Christine Copin, Christophe Roumier, Hélène Aubert, Martine Avenel-Audran, Nathalie Grardel, Stéphanie Poulain, Delphine Staumont-Sallé, Julien Seneschal, Gilles Salles, Kamel Ghomari, Louis Terriou, Christian Leclech, Chafika Morati-Hafsaoui, Franck Morschhauser, Olivier Lambotte, Félix Ackerman, Jacques Trauet, Sandrine Geffroy, Florent Dumezy, Monique Capron, Catherine Roche-Lestienne, Alain Taieb, Pierre-Yves Hatron, Sylvain Dubucquoi, Eric Hachulla, Lionel Prin, Myriam Labalette, David Launay, Claude Preudhomme, and Jean-Emmanuel Kahn

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

The CD3−CD4+ lymphoid variant of hypereosinophilic syndrome is characterized by hypereosinophilia and clonal circulating CD3−CD4+ T cells. Peripheral T-cell lymphoma has been described during this disease course, and we observed in our cohort of 23 patients 2 cases of angio-immunoblastic T-cell lymphoma. We focus here on histopathological (n=12 patients) and immunophenotypic (n=15) characteristics of CD3−CD4+ lymphoid variant of hypereosinophilic syndrome. Atypical CD4+ T cells lymphoid infiltrates were found in 10 of 12 CD3−CD4+ L-HES patients, in lymph nodes (n=4 of 4 patients), in skin (n=9 of 9) and other extra-nodal tissues (gut, lacrymal gland, synovium). Lymph nodes displayed infiltrates limited to the interfollicular areas or even an effacement of nodal architecture, associated with proliferation of arborizing high endothelial venules and increased follicular dendritic cell meshwork. Analysis of 2 fresh skin samples confirmed the presence of CD3−CD4+ T cells. Clonal T cells were detected in at least one tissue in 8 patients, including lymph nodes (n=4 of 4): the same clonal T cells were detected in blood and in at least one biopsy, with a maximum delay of 23 years between samples. In the majority of cases, circulating CD3−CD4+ T cells were CD2hi (n=9 of 14), CD5hi (n=12 of 14), and CD7−(n=4 of 14) or CD7low (n=10 of 14). Angio-immunoblastic T-cell lymphoma can also present with CD3−CD4+ T cells; despite other common histopathological and immunophenotypic features, CD10 expression and follicular helper T-cell markers were not detected in lymphoid variant of hypereosinophilic syndrome patients, except in both patients who developed angio-immunoblastic T-cell lymphoma, and only at T-cell lymphoma diagnosis. Taken together, persistence of tissular clonal T cells and histopathological features define CD3−CD4+ lymphoid variant of hypereosinophilic syndrome as a peripheral indolent clonal T-cell lymphoproliferative disorder, which should not be confused with angio-immunoblastic T-cell lymphoma.

Published
2015
Full Text
View/download PDF

8. Very short insertions in the FLT3 gene are of therapeutic significance in acute myeloid leukemia

Author

Norman, Abbou, Sara, Addakiri, Louis, Adje Missa, Lucille, Altounian, Chloé, Arfeuille, Amélie, Bachelot, Fanny, Baran-Marszak, Kildie, Barrial, Anne, Barthel, Martine, Becker, Emmanuel, Beillard, Graziella, Bernier, Annaëlle, Beucher, Odile, Blanchet, Pauline, Blateau, Julliane, Bloch, Lara, Boucher, Marie-Laure, Boulland, Anne, Bouvier, Simon, Bouzy, Claire, Bracquemart, Clotilde, Bravetti, Chantal, Brouzes, Patricia, Brugel, Serge, Carillo, Bruno, Cassinat, Hélène, Cave, Aurélie, Caye-Eude, Jean-Michel, Cayuela, Carole, Charlot, Aurélie, Chauveau, Sara, Chikhi, Lionel, Chollet, Jean-Claude, Chomel, Emmanuelle, Clappier, Alexis, Claudel, Pascale, Cornillet Lefebvre, Laurane, Cottin, Marie-Magdelaine, Coude, Vincent, Cussac, Bérangère, Dadone-Montaudie, Frédéric, Davi, Véronique, De Mas, Agathe, Debliquis, Matthieu, Decamp, Sabine, Defasque, Michaël, Degaud, Marlene, Dejean, Eric, Delabesse, Hervé, Delacour, Marie-Hélène, Delfau-Larue, Anne, Desmares, Marion, Divoux, Natacha, Doumbadze, Julie, Dremaux, Bernard, Drenou, Stéphanie, Dulucq, Coraline, Dumont, Manon, Duprat, Valérie, Duranton-Tanneur, Marie-Hélène, Estienne, Pascaline, Etancelin, Lisa, Faucheux, Laurène, Fenwarth, Carole, Fleury, Elise, Fournier, Chloé, Friedrich, Xavier, Fund, Nathalie, Gachard, Jean-Baptiste, Gaillard, Coralie, Giot, Valérie, Goncalves, Nathalie, Grardel, Brigitte, Gubler, Yacine, Haddad, Mehdi, Hage Sleiman, Sandrine, Hayette, Claire, Hirschauer, Sarah, Huet, Carole, Humbert, Antoine, Ittel, Sophie, Kaltenbach, Sébastien, Lachot, Sophy, Laibe, Grégory, Lazarian, Valoris, Le Brun, Christelle, Le Sciellour, Benjamin, Lebecque, Isabelle, Lemaire, Melchior, Le Mene, Christine, Lespinasse, Ludovic, Lhermitte, Laurence, Lode, Damien, Luque Paz, Cyril, Maingourd, Elsa, Maitre, Mansier, Olivier, Alice, Marceau-Renaut, Angelique, Marcon, Mélanie, Martin-Gourier, Christophe, Marzac, Claire, Mauduit, Lucie, Maurice, Audrey, Menard, Jean-Philippe, Merlio, Yannick, Miguet Laurent, Djamia, Mokrane, Nathalie, Monhoven, Marie-Joelle, Mozziconacci, Marc, Muller, Anne, Murati-Zeller, Dina, Naguib, Rajiv, Narayanin, Olivier, Nibourel, Pauline, Noyel, Jennifer, Osman, Cédric, Pastoret, Agathe, Paubel, Anne, Perdrix, Benjamin, Podvin, Benoit, Quilichini, Anna, Raimbault, Thimali, Ranaweera Arachchige, Noémie, Ravalet, Julie, Renard, Aline, Renneville, Florian, Renosi, Bénédicte, Ribourtout, David, Rizzo, Camille, Rottier, Léa, Ryffel, Ivan, Sloma, Brigitte, Soubeyran, Nathalie, Sorel, Marc, Spentchian, Assia, Taleb, Thomas, Tassin, Andrei, Tchirkov, Giulia, Tueur, Valérie, Ugo, Laurent, Vallat, Lauren, Veronese, Patrick, Villarese, Margaux, Wiber, Loria, Zalmaï, Tamburini, Jerome, Mouche, Sarah, Larrue, Clement, Duployez, Nicolas, Bidet, Audrey, Salotti, Auriane, Hirsch, Pierre, Rigolot, Lucie, Carras, Sylvain, Templé, Marie, Favale, Fabrizia, Flandrin-Gresta, Pascale, Le Bris, Yannick, Alary, Anne-Sophie, Mauvieux, Laurent, Tondeur, Sylvie, Delabesse, Eric, Delhommeau, François, Sujobert, Pierre, and Kosmider, Olivier

Published
2023
Full Text
View/download PDF

9. Prognostic value and oncogenic landscape of TP53 alterations in adult and pediatric T-ALL

Author

Mathieu Simonin, Guillaume P. Andrieu, Rudy Birsen, Marie Balsat, Guillaume Hypolite, Lucien Courtois, Carlos Graux, Nathalie Grardel, Jean-Michel Cayuela, Françoise Huguet, Yves Chalandon, Yannick Le Bris, Elizabeth Macintyre, Virginie Gandemer, Arnaud Petit, Philippe Rousselot, André Baruchel, Didier Bouscary, Olivier Hermine, Nicolas Boissel, Vahid Asnafi, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service d'hématologie, 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), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Hospices Civils de Lyon (HCL), CHU UCL Namur, CHU Lille, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Lavoisier de Versailles (ILV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Hôpital Robert Debré Paris, Hôpital Robert Debré, Hôpital Cochin [AP-HP], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and CHU Necker - Enfants Malades [AP-HP]

Subjects
[SDV]Life Sciences [q-bio], Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Biology, Hematology, Biochemistry
Abstract

International audience

Published
2023

10. KMT2A-CBL rearrangements in acute leukemias: clinical characteristics and genetic breakpoints

Author

Alex Bataller, Jordi Esteve, Patrice Chevallier, Nathalie Grardel, Mónica López-Guerra, Clara Bueno, Francesca Guijarro, Rolf Marschalek, Sílvia Beà, Aurélie Caye, Jen-Fen Fu, Temenuzhka Boneva, Pablo Menendez, Marion Strullu, Elisabeth P. Nacheva, Arthur Sterin, Claus Meyer, Laura Magnano, Patrizia Larghero, Lee-Yung Shih, Pablo Mozas, Jan Zuna, Oscar Molina, Marketa Zaliova, and Pascale Cornillet-Lefebvre

Subjects
Genetics, KMT2A, Leukemia, Breakpoint, biology.protein, Research Letter, Humans, Hematology, Histone-Lysine N-Methyltransferase, Biology, Myeloid-Lymphoid Leukemia Protein
Published
2021

11. In Adults with Ph-Negative Acute Lymphoblastic Leukemia (ALL), Age-Adapted Chemotherapy Intensity and MRD-Driven Transplant Indication Significantly Reduces Treatment-Related Mortality (TRM) and Improves Overall Survival - Results from the Graall-2014 Trial

Author

Nicolas Boissel, Francoise Huguet, Thibaut Leguay, Hunault-Berger Mathilde, Carlos Graux, Yves Chalandon, Eric Delabesse, Yosr Hicheri, Patrice Chevallier, Marie Balsat, Cedric Pastoret, Martine Escoffre-Barbe, Florence Pasquier, Jean-Pierre Marolleau, Anne Thiebaut-Bertrand, Anne Huynh, Nathalie Dhedin, Emilie Lemasle, Caroline Bonmati, Sébastien Maury, Gaëlle Guillerm, Anna Berceanu, Urs Schanz, Thomas Cluzeau, Pascal Turlure, Philippe Rousselot, Bernard J.M. De Prijck, Nathalie Grardel, Marie C Bene, Marine Lafage, Norbert Ifrah, Veronique Lheritier, Vahid Asnafi, Emmanuelle Clappier, Herve Dombret, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Recherche clinique appliquée à l'hématologie (URP_3518), Université Paris Cité (UPCité), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU UCL Namur, Hôpitaux Universitaires de Genève (HUG), 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], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Pontchaillou [Rennes], Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), CHU Amiens-Picardie, Centre Hospitalier Universitaire [Grenoble] (CHU), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital Henri Mondor, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), University hospital of Zurich [Zurich], Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA), CHU Limoges, Centre Hospitalier de Versailles André Mignot (CHV), CHU Sart Tilman [Liege, Belgium], CHU Lille, Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), CHU d'Angers [Département Urgences], PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Coordination du Groupe GRAALL [CH Lyon-Sud], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), 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), CHU Necker - Enfants Malades [AP-HP], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and DESSAIVRE, Louise

Subjects
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Immunology, Cell Biology, Hematology, Biochemistry, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Background During the 2005-2014 period, the GRAALL conducted the GRAALL-2005 trial in patients (pts) with Philadelphia chromosome (Ph)-negative ALL aged 18-59y. In this trial, all pts received a pediatric-inspired chemotherapy, whatever their age. Post-hoc analysis revealed an unacceptable TRM in pts aged 45-59y (Huguet et al. J Clin Oncol 2018; 36:2514-23). Allogeneic hematopoietic stem cell transplantation (HSCT) was offered in first complete remission (CR) to most CR pts, defined at high-risk (HR) by at least one baseline clinical or biological HR factor (CNS involvement, complex karyotype [≥5 abns.], low hypodiploidy/near triploidy, poor early blast clearance, late CR, as well as WBC ≥ 30x109/L, lack of CD10 expression, KMT2A rearrangement or TCF3::PBX1 fusion for B-cell precursor [BCP] ALL). Minimal residual disease (MRD) response was not considered for HSCT indication at that time.In the next GRAALL-2014 trial conducted in a similar population, we introduced two major changes in the treatment strategy. First, chemotherapy intensity (steroids, anthracycline and L-asparaginase) was reduced in pts aged 45-59y to decrease excessive TRM. Secondly, the indication for HSCT was modified, relying on IG/TR MRD response only (post-induction MRD ≥10-3 and/or post-consolidation MRD ≥10-4) while not on any former baseline HR criterion. Here, we compare the outcomes of the two trials, focusing on the impact of these two major evolutions.Patients & Methods A total of 743 pts treated in the GRAALL-2014 trial between 2015 and 2020 were compared to the 787 pts from the historical GRAALL-2005 trial, in terms of CR and induction death rates, rate of HSCT in CR1, cumulative incidence of TRM (CITRM) and relapse (CIR), relapse-free (RFS) and overall (OS) survival. It should be noted that two nested Phase 2 trials were introduced by amendment during the GRAALL-2014 course (in 2017 and 2018, respectively), aiming to evaluate post-remission addition of nelarabine and blinatumomab in 87 T-ALL and 94 BCP-ALL selected pts, respectively.Results Main patient characteristics, including age, gender, BCP/T-ALL, WBC, and historical baseline HR features, did not significantly differ between the two trial cohorts, even if CNS disease at diagnosis was more frequent in the 2014 cohort (12 vs 7%, p= 0.001).Outcome comparisons are shown in Table 1. Overall, the induction death rate was significantly reduced in the GRAALL-2014 (3 vs 6%, p= 0.005). As expected, this was only observed in pts aged 44-59y (3 vs 11%, p= 0.001), in whom dose-intensity reduction also translated into a higher need for second induction course (9 vs 5%, p= 0.05) eventually resulting in a higher CR rate (92 vs 86%, p= 0.05). Due to the newly introduced MRD-based stratification, the rate of pts with HSCT indication was markedly reduced (30 vs 65%, p

Published
2022

12. Oncogenetic landscape and clinical impact of IDH1 and IDH2 mutations in T-ALL

Author

Arnaud Petit, Etienne Lengliné, Stéphane Ducassou, Elizabeth Macintyre, Françoise Huguet, Nicolas Boissel, Virginie Gandemer, Norbert Ifrah, Jean-Michel Cayuela, Guillaume Andrieu, Vahid Asnafi, Aline Schmidt, Nathalie Grardel, Isabelle Arnoux, Carlos Graux, Christophe Bontoux, Marie-Emilie Dourthe, Mathieu Simonin, Hervé Dombret, Ludovic Lhermitte, André Baruchel, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), 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), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital Robert Debré, Hopital Saint-Louis [AP-HP] (AP-HP), CHU UCL Namur, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Bordeaux [Bordeaux], CHU Pontchaillou [Rennes], UCL - (MGD) Service d'hématologie, UCL - SSS/IREC/MONT - Pôle Mont Godinne, HAL-SU, Gestionnaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Oncology, Cancer Research, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, IDH1, Adolescent, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease_cause, IDH2, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genotype, Humans, Medicine, PTEN, Diseases of the blood and blood-forming organs, Cumulative incidence, Child, Molecular Biology, RC254-282, 030304 developmental biology, 0303 health sciences, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Hematology, biology, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Myeloid leukemia, Middle Aged, Prognosis, Isocitrate Dehydrogenase, 3. Good health, Child, Preschool, 030220 oncology & carcinogenesis, biology.protein, RC633-647.5, business, T-ALL, Rapid Communication, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

IDH1 and IDH2 mutations (IDH1/2Mut) are recognized as recurrent genetic alterations in acute myeloid leukemia (AML) and associated with both clinical impact and therapeutic opportunity due to the recent development of specific IDH1/2Mut inhibitors. In T-cell acute lymphoblastic leukemia (T-ALL), their incidence and prognostic implications remain poorly reported. Our targeted next-generation sequencing approach allowed comprehensive assessment of genotype across the entire IDH1 and IDH2 locus in 1085 consecutive unselected and newly diagnosed patients with T-ALL and identified 4% of, virtually exclusive (47 of 49 patients), IDH1/2Mut. Mutational patterns of IDH1/2Mut in T-ALL present some specific features compared to AML. Whereas IDH2R140Q mutation was frequent in T-ALL (25 of 51 mutations), the IDH2R172 AML hotspot was absent. IDH2 mutations were associated with older age, an immature phenotype, more frequent RAS gain-of-function mutations and epigenetic regulator loss-of-function alterations (DNMT3A and TET2). IDH2 mutations, contrary to IDH1 mutations, appeared to be an independent prognostic factor in multivariate analysis with the NOTCH1/FBXW7/RAS/PTEN classifier. IDH2Mut were significantly associated with a high cumulative incidence of relapse and very dismal outcome, suggesting that IDH2-mutated T-ALL cases should be identified at diagnosis in order to benefit from therapeutic intensification and/or specific IDH2 inhibitors.

Published
2021

13. Clinical and biological features of PTPN2-deleted adult and pediatric T-cell acute lymphoblastic leukemia

Author

Mathieu Simonin, Arnaud Petit, Hervé Dombret, Elizabeth Macintyre, Marie Emilie Dourthe, Ludovic Lhermitte, Yves Chalandon, Mehdi Latiri, Marion Alcantara, Vahid Asnafi, André Baruchel, Nicolas Boissel, Carlos Graux, Nathalie Grardel, Norbert Ifrah, Aurore Touzart, Jean Michel Cayuela, UCL - (MGD) Service d'hématologie, and UCL - SSS/IREC/MONT - Pôle Mont Godinne

Subjects
Adult, Male, STAT Transcription Factors/metabolism, Tumor suppressor gene, Adolescent, Genotype, Phosphatase, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Immunophenotyping, Interleukin-7 Receptor alpha Subunit, Young Adult, Gene Frequency, Biomarkers, Tumor, Medicine, Tensin, PTEN, Humans, Cumulative incidence, Interleukin-7 receptor, Alleles, Janus Kinases, Sequence Deletion, ddc:616, Protein Tyrosine Phosphatase, Non-Receptor Type 2, Lymphoid Neoplasia, biology, business.industry, Protein Tyrosine Phosphatase, Non-Receptor Type 2/deficiency, High-Throughput Nucleotide Sequencing, Hematology, Middle Aged, Prognosis, STAT Transcription Factors, Cancer research, biology.protein, Janus Kinases/metabolism, Female, business, Interleukin-7 Receptor alpha Subunit/genetics/metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis/genetics/mortality/therapy
Abstract

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a phosphatase known to be a tumor suppressor gene in T-cell acute lymphoblastic leukemia (T-ALL). Because the full clinicobiologic characteristics of PTPN2 loss remain poorly reported, we aimed to provide a comprehensive analysis of PTPN2 deletions within a cohort of 430 patients, including 216 adults and 214 children treated according to the GRAALL03/05 (#NCT00222027 and #NCT00327678) and the FRALLE2000 protocols, respectively. We used multiplex ligation-dependent probe amplification to identify an 8% incidence of PTPN2 deletion, which was comparable in adult (9%) and pediatric (6%) populations. PTPN2 deletions were significantly associated with an αβ lineage and TLX1 deregulation. Analysis of the mutational genotype of adult T-ALL revealed a positive correlation between PTPN2 deletions and gain-of-function alterations in the IL7R/JAK-STAT signaling pathway as well as PHF6 and WT1 mutations. Of note, PTPN2 and PTEN (phosphatase and tensin homolog) deletions were mutually exclusive. Regarding treatment response, PTPN2-deleted T-ALLs were associated with a higher glucocorticoid response and a trend for improved survival in children, but not in adults, with a 5-year cumulative incidence of relapse of 8% for PTPN2-deleted pediatric cases vs 26% (P = .177).

Published
2019

14. 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

15. Differential impact of drugs on the outcome of ETV6-RUNX1 positive childhood B-cell precursor acute lymphoblastic leukaemia

Author

Claire Freycon, P Rohrlich, Sandrine Girard, Hélène Cavé, Koen Norga, Geneviève Plat, Yves Bertrand, M. F. Dresse, Karima Yakouben, Emmanuelle Clappier, Christophe Chantrain, Maryline Poiree, Patrick Lutz, Pauline Simon, Françoise Mazingue, Nathalie Grardel, Nicolas Sirvent, Claire Pluchart, Frédéric Millot, Stefan Suciu, Vitor Costa, Anne Uyttebroeck, Nicole Dastugue, Odile Minckes, Caroline Gilotay, Caroline Piette, J van der Werff Ten Bosch, N. Van Roy, Séverine Drunat, Yves Benoit, A Ferster, Faculty of Medicine and Pharmacy, Clinical sciences, and Growth and Development

Subjects
Oncology, Male, medicine.medical_specialty, Cancer Research, Adolescent, Oncogene Proteins, Fusion, Antineoplastic Agents, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Etv6 runx1, hemic and lymphatic diseases, Internal medicine, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Medicine, Humans, Child, B cell, Dexamethasone, Differential impact, B-Lymphocytes, Proto-Oncogene Proteins c-ets, business.industry, hematology, Cancer, Infant, medicine.disease, humanities, Repressor Proteins, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Child, Preschool, Core Binding Factor Alpha 2 Subunit, oncology, Lymphoblastic leukaemia, Female, Human medicine, business, 030215 immunology, medicine.drug
Abstract

Differential impact of drugs on the outcome of ETV6-RUNX1 positive childhood B-cell precursor acute lymphoblastic leukaemia: results of the EORTC CLG 58881 and 58951 trials

Published
2018

16. High-throughput sequencing in acute lymphoblastic leukemia: Follow-up of minimal residual disease and emergence of new clones

Author

Yann Ferret, Marc Duez, Tatiana Rocher, Nicolas Duployez, Sabine Quief, Martin Figeac, Aurélie Caillault, Shéhérazade Sebda, Ryan Herbert, Céline Villenet, Nathalie Grardel, Mikaël Salson, Mathieu Giraud, Claude Preudhomme, Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Bioinformatics and Sequence Analysis (BONSAI), Centre National de la Recherche Scientifique (CNRS)-Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies-Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Picardie Jules Verne (UPJV), School of Social and Community Medicine [Bristol], University of Bristol [Bristol], Site de Recherche Intégrée en Cancérologie (SIRIC-ONCOLille), Université de Lille, Sciences et Technologies-Université de Lille, Sciences Humaines et Sociales-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Plateforme de génomique fonctionnelle et structurelle [Lille], Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Université de Lille, Droit et Santé, Université de Lille, Sciences et Technologies-Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Université de Lille-UNICANCER-Université de Lille-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
0301 basic medicine, Cancer Research, Neoplasm, Residual, Bioinformatics, Lymphoblastic Leukemia, Population, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Bone Marrow, Monitoring, Immunologic, hemic and lymphatic diseases, medicine, Humans, education, Retrospective Studies, Minimal Residual Disease, education.field_of_study, biology, Follow-up, Repertoire Sequencing, Genes, T-Cell Receptor gamma, High-Throughput Nucleotide Sequencing, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Acute Lymphoblastic Leukemia, Minimal residual disease, 3. Good health, Clone Cells, 030104 developmental biology, medicine.anatomical_structure, Real-time polymerase chain reaction, Oncology, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Hematological neoplasm, Bone marrow, Antibody, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Immunoglobulin Heavy Chains, Software, 030215 immunology, Follow-Up Studies
Abstract

International audience; Minimal residual disease (MRD) is known to be an independent prognostic factor in patients with acute lymphoblastic leukemia (ALL). High-throughput sequencing (HTS) is currently used in routine practice for the diagnosis and follow-up of patients with hematological neoplasms. In this retrospective study, we examined the role of immunoglobulin/T-cell receptor-based MRD in patients with ALL by HTS analysis of immunoglobulin H and/or T-cell receptor gamma chain loci in bone marrow samples from 11 patients with ALL, at diagnosis and during follow-up. We assessed the clinical feasibility of using combined HTS and bioinformatics analysis with interactive visualization using Vidjil software. We discuss the advantages and drawbacks of HTS for monitoring MRD. HTS gives a more complete insight of the leukemic population than conventional real-time quantitative PCR (qPCR), and allows identification of new emerging clones at each time point of the monitoring. Thus, HTS monitoring of Ig/TCR based MRD is expected to improve the management of patients with ALL.

Published
2017

17. Diagnosis of intrachromosomal amplification of chromosome 21 (iAMP21) by molecular cytogenetics in pediatric acute lymphoblastic leukemia

Author

Guillaume Grzych, Catherine Roche-Lestienne, Claude Preudhomme, Gauthier Decool, Nicolas Duployez, Elise Boudry-Labis, Wadih Abou Chahla, and Nathalie Grardel

Subjects
Genetics, Poor prognosis, medicine.medical_specialty, RUNX1, business.industry, BCP-ALL, Cytogenetics, General Medicine, Case Reports, cytogenetics, Molecular cytogenetics, SNP-array, chemistry.chemical_compound, Pediatric Acute Lymphoblastic Leukemia, chemistry, Cancer research, medicine, SNP, Chromosome 21, business, SNP array, iAMP21
Abstract

Key Clinical Message Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with poor prognosis that should be investigated in routine practice. Single-nucleotide polymorphism (SNP)-array provides a useful method to detect such cases showing a highly characteristic profile.

Published
2015

18. CD200/BTLA deletions in pediatric precursor B-cell acute lymphoblastic leukemia treated according to the EORTC-CLG 58951 protocol

Author

Magali Meul, Vitor Costa, Nadine Van Roy, Frank Speleman, Karima Yakouben, Yves Benoit, Hélène Cavé, Yves Bertrand, Marilyne Poirée, Jutte van der Werff ten Bosch, Pieter Van Vlierberghe, Alina Ferster, Anne Uyttebroeck, Odile Minckes, Tim Lammens, Hetty Helsmoortel, Emmanuel Plouvier, Geneviève Plat, Marleen Bakkus, Françoise Mazingue, Nathalie Grardel, Farzaneh Ghazavi, Samira Zegrari, Jan Philippé, Stefan Suciu, Emmanuelle Clappier, Barbara De Moerloose, Aurélie Caye, Hematology, Clinical sciences, and Growth and Development

Subjects
Oncology, Male, IMPACT, CHILDHOOD, Kaplan-Meier Estimate, THERAPY, law.invention, Chromosome Breakpoints, Gene Frequency, law, Recurrence, Antineoplastic Combined Chemotherapy Protocols, Medicine and Health Sciences, Receptors, Immunologic, Child, Polymerase chain reaction, education.field_of_study, Clinical Trials as Topic, Comparative Genomic Hybridization, Hazard ratio, Hematology, Articles, Prognosis, GENOMIC CHARACTERIZATION, Child, Preschool, TRIAL, Female, medicine.medical_specialty, Adolescent, DNA Copy Number Variations, Population, Copy number analysis, BTLA, Biology, IKZF1 DELETIONS, HODGKIN-LYMPHOMA, Antigens, CD, Internal medicine, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, medicine, Humans, Allele, education, ERG DELETION, Alleles, Proportional hazards model, Infant, Newborn, IKAROS, Infant, Immunology, GENETIC ALTERATIONS, Gene Deletion, Comparative genomic hybridization
Abstract

DNA copy number analysis has been instrumental for the identification of genetic alterations in B-cell precursor acute lymphoblastic leukemia. Notably, some of these genetic defects have been associated with poor treatment outcome and might be relevant for future risk stratification. In this study, we characterized recurrent deletions of CD200 and BTLA genes, mediated by recombination-activating genes, and used breakpoint-specific polymerase chain reaction assay to screen a cohort of 1154 cases of B-cell precursor acute lymphoblastic leukemia uniformly treated according to the EORTC-CLG 58951 protocol. CD200/BTLA deletions were identified in 56 of the patients (4.8%) and were associated with an inferior 8-year event free survival in this treatment protocol [70.2% ± 1.2% for patients with deletions versus 83.5% ± 6.4% for non-deleted cases (hazard ratio 2.02; 95% confidence interval 1.23-3.32; P=0.005)]. Genetically, CD200/BTLA deletions were strongly associated with ETV6-RUNX1-positive leukemias (P

Published
2015

19. Follow-up of post-transplant minimal residual disease and chimerism in childhood lymphoblastic leukaemia: 90 d to react

Author

Jean-François Eliaou, Cécile Pochon, Pierre Bordigoni, Pierre Rohrlich, Alexandra Salmon, Gérard Michel, Pascale Schneider, Séverine Drunat, Nathalie Grardel, François Demeocq, Emmanuel Oger, Catherine Paillard, Philippe Jonveaux, Jean-Michel Cayuela, Gilbert Semana, Hélène Cavé, Jean-Hugues Dalle, Yves Bertrand, Geneviève Margueritte, Francoise Mechinaud, Virginie Gandemer, Marilyne Poirée, Dominique Plantaz, Brigitte Nelken, Elizabeth Macintyre, Service d'Urologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), CIC-IT Rennes, Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pharmacologie [Rennes], CHU Pontchaillou [Rennes], Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital Robert Debré Paris, Hôpital Robert Debré, Service d'Hématologie-Oncologie Pédiatrique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire central d'hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'hématologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de pédiatrie, CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Service d'hématologie pédiatrique, CHU Clermont-Ferrand, Service de pédiatrie médicale et médecine de l'adolescent [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service Hématologie Infantile, Hopital L'Archet-II, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), RENNES - Centre de Transfusion Sanguine (RENNES - CTS), Centre de Transfusion Sanguine - RENNES, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Unité de Transplantation Médullaire, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Hôpital d'enfants, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Hématogoie pédiatrique, 2003, Public Health Research Programme, and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Oncology, Male, medicine.medical_specialty, Neoplasm, Residual, medicine.medical_treatment, Lymphocyte, [SDV]Life Sciences [q-bio], Graft vs Host Disease, stem cell transplantation, childhood leukaemia, Internal medicine, hemic and lymphatic diseases, medicine, Humans, Lymphocytes, Child, Proportional Hazards Models, Transplantation Chimera, business.industry, Hazard ratio, Hematopoietic Stem Cell Transplantation, Hematology, Immunotherapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Ciclosporin, Prognosis, Minimal residual disease, Adoptive Transfer, Tissue Donors, 3. Good health, Surgery, Transplantation, medicine.anatomical_structure, Treatment Outcome, chimerism, Cohort, minimal residual disease, Lymphoblastic leukaemia, Female, immunotherapy, business, medicine.drug, Follow-Up Studies
Abstract

International audience; Relapse after transplantation is a major cause of treatment failure in paediatric acute lymphoblastic leukaemia (ALL). Here, we report the findings of a prospective national study designed to investigate the feasibility of immune intervention in children in first or subsequent remission following myeloablative conditioning. This study included 133 children who received a transplant for ALL between 2005 and 2008. Minimal Residual Disease (MRD) based on T cell receptor/immunoglobulin gene rearrangements was measured on days -30, 30, 90 and 150 post-transplantation. Ciclosporin treatment was rapidly discontinued and donor lymphocyte infusions (DLI) were programmed for patients with a pre- or post-transplant MRD status ≥10(-3) . Only nine patients received DLI. Pre- and post-transplant MRD status, and the duration of ciclosporin were independently associated with 5-year overall survival (OS), which was 62·07% for the whole cohort. OS was substantially higher in patients cleared of MRD than in those with persistent MRD (52·3% vs. 14·3%, respectively). Only pre-transplant MRD status (Hazard Ratio 2·57, P = 0·04) and duration of ciclosporin treatment (P < 0·001) were independently associated with relapse. The kinetics of chimerism were not useful for predicting relapse, whereas MRD monitoring up to 90 d post-transplantation was a valuable prognostic tool to guide therapeutic intervention.

Published
2015

20. P315: TP53 ALTERATIONS AND MRD REFINE PROGNOSIS OF ADULT KMT2A-REARRANGED B-ALL.

Author

Kim, Rathana, Bergugnat, Hugo, Pasquier, Florence, Raffoux, Emmanuel, Larcher, Lise, Passet, Marie, Pastoret, Cedric, Nathalie, Grardel, Asnafi, Vahid, Delabesse, Eric, Caye-Eude, Aurélie, Meyer, Claus, Masrschalek, Rolf, Thiebaut-Bertrand, Anne, Balsat, Marie, Escoffre, Martine, Blum, Sabine, Baumann, Michael, Banos, Anne, and Straetmans, Nicole

Published
2023
Full Text
View/download PDF

21. Clinical value of pre-transplant minimal residual disease in childhood lymphoblastic leukaemia: the results of the French minimal residual disease-guided protocol

Author

Elizabeth Macintyre, Pascale Schneider, Claire Galambrun, Cécile Pochon, Jean-Hugues Dalle, Pierre Bordigoni, Virginie Gandemer, Geneviève Margueritte, Gérard Michel, Patrick Lutz, Claudine Schmitt, Eva de Berranger, Emmanuel Oger, Hélène Cavé, François Demeocq, Marilyne Poirée, Nathalie Grardel, Jean-Michel Cayuela, Francoise Mechinaud, Pierre Rorhlich, Dominique Plantaz, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Pharmacologie [Rennes], CHU Pontchaillou [Rennes], Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Université Paris Diderot - Paris 7 (UPD7), Service de Biochimie Génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Laboratoire central d'hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Children's Cancer Center, The Royal Children's Hospital, Hôpital Civil, Hopital Civil, Service d'hématologie pédiatrique, CHU Clermont-Ferrand, Service d'hémato-immuno-oncologie pédiatrique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service Hématologie Infantile, CHU Grenoble, Unité de Transplantation Médullaire, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Hôpital d'enfants, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
Oncology, Male, medicine.medical_specialty, Neoplasm, Residual, Multivariate analysis, Adolescent, medicine.medical_treatment, Hematopoietic stem cell transplantation, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Adjuvants, Immunologic, Immunologic, Internal medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, medicine, Combined Modality Therapy, Humans, Cumulative incidence, Adjuvants, Prospective Studies, Prospective cohort study, Child, Preschool, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Remission Induction, Hematopoietic Stem Cell Transplantation, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, Minimal residual disease, 3. Good health, Surgery, Transplantation, body regions, Treatment Outcome, Child, Preschool, 030220 oncology & carcinogenesis, Residual, Lymphoblastic leukaemia, Neoplasm, Female, business, 030215 immunology
Abstract

International audience; Minimal residual disease (MRD) is a major predictive factor of the cure rate of acute lymphoblastic leukaemia (ALL). Haematopoietic cell transplantation is a treatment option for patients at high risk of relapse. Between 2005 and 2008, we conducted a prospective study evaluating the feasibility and efficacy of the reduction of immunosuppressive medication shortly after a non-ex vivo T depleted myeloablative transplantation. Immunoglobulin (Ig)H/T-cell receptor MRD 30 d before transplant could be obtained in 122 of the 133 cases of high-risk paediatric ALL enrolled. There were no significant demographic differences except remission status (first or second complete remission) between the 95 children with MRD \textless10(-3) and the 27 with MRD ≥10(-3) . Multivariate analysis identified sex match and MRD as being significantly associated with 5-year survival. MRD ≥10(-3) compromised the 5-year cumulative incidence of relapse (43*6 vs. 16*7%). Complete remission status and stem cell source did not modify the relationship between MRD and prognosis. Thus, pre-transplant MRD is still a major predictor of outcome for ALL. The MRD-guided strategy resulted in survival for 72*3% of patients with MRD\textless10(-3) and 40*4% of those with MRD ≥10(-3).

Published
2014

22. Genetic polymorphisms in ARID5B, CEBPE, IKZF1 and CDKN2A in relation with risk of acute lymphoblastic leukaemia in adults: a Group for Research on Adult Acute Lymphoblastic Leukaemia (GRAALL) study

Author

Eric Delabesse, Xavier Thomas, Véronique Lhéritier, Nicolas Pottier, Jean-Yves Cahn, Elizabeth Macintyre, Soizic Guihard, Nathalie Grardel, Meyling Cheok, Arnaud Pigneux, Céline Berthon, Hervé Dombret, Norbert Ifrah, Pauline Peyrouze, Marie C. Béné, 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), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Impact de l'environnement chimique sur la santé humaine - ULR 4483 (IMPECS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), TheREx, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), 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), Service d'Immunologie [CHRU Nancy], 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), 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Lymphocyte et cancer, IFR105-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie clinique [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Institut Cochin ( 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 ), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Impact de l'Environnement Chimique sur la Santé Humain, PRES Université Lille Nord de France, Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), 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 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre de Recherche en Cancérologie de Lyon ( 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 ), IFR105-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne-Université Paris 13 ( UP13 ), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, 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), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, 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), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], 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), and Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Avicenne

Subjects
Male, MESH : Transcription Factors, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: CCAAT-Enhancer-Binding Proteins, 0302 clinical medicine, CDKN2A, MESH : Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH : Female, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, Hematology, MESH: Transcription Factors, MESH: Ikaros Transcription Factor, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH : Adult, 3. Good health, DNA-Binding Proteins, MESH : CCAAT-Enhancer-Binding Proteins, MESH: Young Adult, 030220 oncology & carcinogenesis, Female, MESH : DNA-Binding Proteins, Adult, MESH : Male, MESH : Young Adult, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Ikaros Transcription Factor, Young Adult, MESH : Ikaros Transcription Factor, Humans, Genetic Predisposition to Disease, MESH : Middle Aged, 030304 developmental biology, MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH: Humans, MESH : Humans, MESH: Adult, CEBPE, MESH: Male, Immunology, CCAAT-Enhancer-Binding Proteins, Lymphoblastic leukaemia, MESH : Genetic Predisposition to Disease, MESH: Female, MESH: DNA-Binding Proteins, Transcription Factors
Abstract

International audience

Published
2012

23. Genomic characterization of Imatinib resistance in CD34+ cell populations from chronic myeloid leukaemia patients

Author

Catherine Roche-Lestienne, Gabriel Etienne, Christophe Roumier, Véronique Maguer-Satta, Eric Lippert, François Guilhot, Bruno Quesnel, Selim Corm, Nathalie Grardel, Thierry Idziorek, Franck E. Nicolini, Sami Joha, Jean-Luc Laï, Claude Preudhomme, Frédéric Leprêtre, Martin Figeac, Olivier Nibourel, Véronique Dauphin, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, 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), Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP), Université de Poitiers-Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'hématologie, CHU Bordeaux [Bordeaux], Laboratoire d'Hématologie Biologique, Centre de biologie Pathologie PM Degand, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Functional Genomic Platform, UMR 837 INSERM, Equipe 11, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Poitiers-Institut de Chimie du CNRS (INC)

Subjects
Genome instability, Cancer Research, Pathology, T-Lymphocytes, Gene Dosage, CD34, MESH: Piperazines, Antigens, CD34, Disease, Piperazines, MESH: Gene Dosage, 0302 clinical medicine, hemic and lymphatic diseases, MESH: In Situ Hybridization, Fluorescence, In Situ Hybridization, Fluorescence, Chromosome 7 (human), Comparative Genomic Hybridization, 0303 health sciences, Hematology, MESH: Genes, abl, MESH: Ikaros Transcription Factor, MESH: Drug Resistance, Neoplasm, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Benzamides, Imatinib Mesylate, Chromosomes, Human, Pair 7, medicine.drug, medicine.medical_specialty, MESH: Chromosomes, Human, Pair 7, MESH: Mutation, Antineoplastic Agents, Locus (genetics), [SDV.CAN]Life Sciences [q-bio]/Cancer, Genes, abl, Biology, Chronic myeloid leukaemia, Ikaros Transcription Factor, 03 medical and health sciences, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, medicine, Humans, 030304 developmental biology, Chromosomes, Human, Pair 12, MESH: Humans, Chromosomes, Human, Pair 13, Imatinib resistance, Imatinib, MESH: Antigens, CD34, MESH: Comparative Genomic Hybridization, Pyrimidines, MESH: T-Lymphocytes, MESH: Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Drug Resistance, Neoplasm, MESH: Pyrimidines, Mutation, MESH: Genome-Wide Association Study, Cancer research, MESH: Antineoplastic Agents, MESH: Chromosomes, Human, Pair 13, MESH: Chromosomes, Human, Pair 12, Genome-Wide Association Study
Abstract

International audience; To ascertain genomic alterations associated with Imatinib resistance in chronic myeloid leukaemia, we performed high resolution genomic analysis of CD34(+) cells from 25 Imatinib (IM) resistant and 11 responders CML patients. Using patients' T-cells as reference, we found significant association between number of acquired cryptic copy number alterations (CNA) and disease phase (p=0.036) or loss of IM response for patients diagnosed in chronic phase (CP) (p=0.04). Recurrent cryptic losses were identified on chromosomes 7, 12 and 13. On chromosome 7, recurrent deletions of the IKZF1 locus were detected, for the first time, in 4 patients in CP.

Published
2011

24. PAX5 mutations occur frequently in adult B-cell progenitor acute lymphoblastic leukemia and PAX5 haploinsufficiency is associated with BCR-ABL1 and TCF3-PBX1 fusion genes: a GRAALL study

Author

Etienne Coyaud, Norbert Ifrah, Nicole Dastugue, M C Béné, Kheira Beldjord, André Delannoy, Eric Delabesse, J M Cayuela, Pierre Brousset, Cyril Broccardo, J Soulier, Claude Preudhomme, Marina Bousquet, Hélène Cavé, Julien Familiades, Marina Lafage-Pochitaloff, Odile Blanchet, F. Huguet, Hervé Dombret, Yves Chalandon, Sophie Dobbelstein, Cathy Quelen, V Lhéritier, E Macintyre, Stéphanie Struski, Nais Prade-Houdellier, Nathalie Grardel, J. De Vos, and Arnaud Pigneux

Subjects
Cancer Research, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics, Fusion Proteins, bcr-abl, Gene Dosage, medicine.disease_cause, Piperazines, Fusion gene, Loss of heterozygosity, immune system diseases, hemic and lymphatic diseases, Basic Helix-Loop-Helix Transcription Factors, Multicenter Studies as Topic, Immunoglobulin Heavy Chains/genetics, Prospective Studies, ddc:616, Mutation, Pre-B-Cell Leukemia Transcription Factor 1, breakpoint cluster region, Hematology, Genomics, Middle Aged, Prognosis, DNA-Binding Proteins, Oncology, Benzamides, Imatinib Mesylate, Haploinsufficiency, Immunoglobulin Heavy Chains, Adult, Adolescent, Antineoplastic Agents, Biology, Gene Rearrangement, T-Lymphocyte, Immunophenotyping, Young Adult, Clinical Trials, Phase II as Topic, Acute lymphocytic leukemia, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Proto-Oncogene Proteins, medicine, Humans, Point Mutation, Basic Helix-Loop-Helix Transcription Factors/genetics, Fusion Proteins, bcr-abl/genetics, Gene Rearrangement, T-Lymphocyte/genetics, Point mutation, PAX5 Transcription Factor, Antineoplastic Agents/therapeutic use, Pyrimidines/therapeutic use, medicine.disease, Piperazines/therapeutic use, B-Cell-Specific Activator Protein/genetics, Proto-Oncogene Proteins/genetics, Pyrimidines, Haplotypes, Cancer research, Carcinogenesis, DNA-Binding Proteins/genetics
Abstract

Adult and child B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) differ in terms of incidence and prognosis. These disparities are mainly due to the molecular abnormalities associated with these two clinical entities. A genome-wide analysis using oligo SNP arrays recently demonstrated that PAX5 (paired-box domain 5) is the main target of somatic mutations in childhood BCP-ALL being altered in 38.9% of the cases. We report here the most extensive analysis of alterations of PAX5 coding sequence in 117 adult BCP-ALL patients in the unique clinical protocol GRAALL-2003/GRAAPH-2003. Our study demonstrates that PAX5 is mutated in 34% of adult BCP-ALL, mutations being partial or complete deletion, partial or complete amplification, point mutation or fusion gene. PAX5 alterations are heterogeneous consisting in complete loss in 17%, focal deletions in 10%, point mutations in 7% and translocations in 1% of the cases. PAX5 complete loss and PAX5 point mutations differ. PAX5 complete loss seems to be a secondary event and is significantly associated with BCR-ABL1 or TCF3-PBX1 fusion genes and a lower white blood cell count.

Published
2009

26. Fast multiclonal clusterization of V(D)J recombinations from high-throughput sequencing

Author

Céline Villenet, Mikaël Salson, Mathieu Giraud, Nathalie Grardel, Christophe Roumier, Marc Duez, Martin Figeac, Sabine Quief, Aurélie Caillault, Claude Preudhomme, Giraud, Mathieu, Laboratoire d'Informatique Fondamentale de Lille (LIFL), Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique (CNRS), Bioinformatics and Sequence Analysis (BONSAI), Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique (CNRS)-Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria), Site de Recherche Intégrée en Cancérologie (SIRIC-ONCOLille), Université de Lille, Sciences et Technologies-Université de Lille, Sciences Humaines et Sociales-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Plateforme de génomique fonctionnelle et structurelle [Lille], Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Université de Lille, Droit et Santé, Institut pour la recherche sur le cancer de Lille [Lille] (IRCL), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de recherche sur le cancer, Institut National de la Santé et de la Recherche Médicale (INSERM), Research supported by SIRIC ONCOLille (Grant INCa-DGOS-Inserm 6041) and by Région Nord-Pas-de-Calais (ABILES), Vidjil - http://www.vidjil.org, and Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
clone (Java method), Neoplasm, Residual, [SDV.IMM] Life Sciences [q-bio]/Immunology, Sequence analysis, Repertoire sequencing (Rep-Seq), Immunology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Germline, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, medicine, Genetics, Humans, Repertoire sequencing, [INFO.INFO-DL]Computer Science [cs]/Digital Libraries [cs.DL], V(D)J recombinations, 030304 developmental biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, High-throughput sequencing, Leukemia, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Methodology Article, V(D)J recombination, Minimal residual disease follow-up, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, Minimal residual disease, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], V(D)J Recombination, [SDV.IMM]Life Sciences [q-bio]/Immunology, DNA microarray, [INFO.INFO-DL] Computer Science [cs]/Digital Libraries [cs.DL], [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Algorithms, Software, 030215 immunology, Biotechnology
Abstract

Background V(D)J recombinations in lymphocytes are essential for immunological diversity. They are also useful markers of pathologies. In leukemia, they are used to quantify the minimal residual disease during patient follow-up. However, the full breadth of lymphocyte diversity is not fully understood. Results We propose new algorithms that process high-throughput sequencing (HTS) data to extract unnamed V(D)J junctions and gather them into clones for quantification. This analysis is based on a seed heuristic and is fast and scalable because in the first phase, no alignment is performed with germline database sequences. The algorithms were applied to TR γ HTS data from a patient with acute lymphoblastic leukemia, and also on data simulating hypermutations. Our methods identified the main clone, as well as additional clones that were not identified with standard protocols. Conclusions The proposed algorithms provide new insight into the analysis of high-throughput sequencing data for leukemia, and also to the quantitative assessment of any immunological profile. The methods described here are implemented in a C++ open-source program called Vidjil. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-409) contains supplementary material, which is available to authorized users.

Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results