99 results on '"Isabelle Radford–Weiss"'
Search Results
2. Somatic genetic rescue of a germline ribosome assembly defect
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Shengjiang Tan, Laëtitia Kermasson, Christine Hilcenko, Vasileios Kargas, David Traynor, Ahmed Z. Boukerrou, Norberto Escudero-Urquijo, Alexandre Faille, Alexis Bertrand, Maxim Rossmann, Beatriz Goyenechea, Li Jin, Jonathan Moreil, Olivier Alibeu, Blandine Beaupain, Christine Bôle-Feysot, Stefano Fumagalli, Sophie Kaltenbach, Jean-Alain Martignoles, Cécile Masson, Patrick Nitschké, Mélanie Parisot, Aurore Pouliet, Isabelle Radford-Weiss, Frédéric Tores, Jean-Pierre de Villartay, Mohammed Zarhrate, Ai Ling Koh, Kong Boo Phua, Bruno Reversade, Peter J. Bond, Christine Bellanné-Chantelot, Isabelle Callebaut, François Delhommeau, Jean Donadieu, Alan J. Warren, and Patrick Revy
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Science - Abstract
Shwachman-Diamond syndrome (SDS) is a leukemia predisposition disorder that is caused by defective release of eIF6 during ribosome assembly. Here the authors show that acquired somatic EIF6 mutations are frequent in the hematopoietic cells from individuals with SDS and provide a selective advantage over non-modified cells.
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- 2021
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3. Publisher Correction: Somatic genetic rescue of a germline ribosome assembly defect
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Shengjiang Tan, Laëtitia Kermasson, Christine Hilcenko, Vasileios Kargas, David Traynor, Ahmed Z. Boukerrou, Norberto Escudero-Urquijo, Alexandre Faille, Alexis Bertrand, Maxim Rossmann, Beatriz Goyenechea, Li Jin, Jonathan Moreil, Olivier Alibeu, Blandine Beaupain, Christine Bôle-Feysot, Stefano Fumagalli, Sophie Kaltenbach, Jean-Alain Martignoles, Cécile Masson, Patrick Nitschké, Mélanie Parisot, Aurore Pouliet, Isabelle Radford-Weiss, Frédéric Tores, Jean-Pierre de Villartay, Mohammed Zarhrate, Ai Ling Koh, Kong Boo Phua, Bruno Reversade, Peter J. Bond, Christine Bellanné-Chantelot, Isabelle Callebaut, François Delhommeau, Jean Donadieu, Alan J. Warren, and Patrick Revy
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Science - Published
- 2022
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4. 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
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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
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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.
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- 2016
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5. Functional analysis of the NUP98-CCDC28A fusion protein
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Arnaud Petit, Christine Ragu, Gwendoline Soler, Chris Ottolenghi, Caroline Schluth, Isabelle Radford-Weiss, Sylvie Schneider-Maunoury, Isabelle Callebaut, Nicole Dastugue, Harry A. Drabkin, Olivier A. Bernard, Serge Romana, and Virginie Penard-Lacronique
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background The nucleoporin gene NUP98 is rearranged in more than 27 chromosomal abnormalities observed in childhood and adult, de novo and therapy-related acute leukemias of myeloid and T-lymphoid origins, resulting in the creation of fusion genes and the expression of chimeric proteins. We report here the functional analysis of the NUP98-coiled-coil domain-containing protein 28A (NUP98-CCDC28A) fusion protein, expressed as the consequence of a recurrent t(6;11)(q24.1;p15.5) translocation.Design and Methods To gain insight into the function of the native CCDC28A gene, we collected information on any differential expression of CCDC28A among normal hematologic cell types and within subgroups of acute leukemia. To assess the in vivo effects of the NUP98-CCDC28A fusion, NUP98-CCDC28A or full length CCDC28A were retrovirally transduced into primary murine bone marrow cells and transduced cells were next transplanted into sub-lethally irradiated recipient mice.Results Our in silico analyses supported a contribution of CCDC28A to discrete stages of murine hematopoietic development. They also suggested selective enrichment of CCDC28A in the French-American-British M6 class of human acute leukemia. Primary murine hematopoietic progenitor cells transduced with NUP98-CCDC28A generated a fully penetrant and transplantable myeloproliferative neoplasm-like myeloid leukemia and induced selective expansion of granulocyte/macrophage progenitors in the bone marrow of transplanted recipients, showing that NUP98-CCDC28A promotes the proliferative capacity and self-renewal potential of myeloid progenitors. In addition, the transformation mediated by NUP98-CCDC28A was not associated with deregulation of the Hoxa-Meis1 pathway, a feature shared by a diverse set of NUP98 fusions.Conclusions Our results demonstrate that the recurrent NUP98-CCDC28A is an oncogene that induces a rapid and transplantable myeloid neoplasm in recipient mice. They also provide additional evidence for an alternative leukemogenic mechanism for NUP98 oncogenes.
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- 2012
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6. Epstein-Barr virus-induced gene 3 (EBI3): a novel diagnosis marker in Burkitt lymphoma and diffuse large B-cell lymphoma.
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Julie Gonin, Frédérique Larousserie, Christian Bastard, Jean-Michel Picquenot, Jérôme Couturier, Isabelle Radford-Weiss, Céline Dietrich, Nicole Brousse, Marie-Cécile Vacher-Lavenu, and Odile Devergne
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Medicine ,Science - Abstract
The distinction between Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), two types of mature aggressive B-cell lymphomas that require distinct treatments, can be difficult because of forms showing features intermediate between DLBCL and BL (here called BL/DLBCL). They can be discriminated by the presence of c-myc translocations characteristic of BL. However, these are not exclusive of BL and when present in DLBCL are associated with lower survival. In this study, we show that Epstein-Barr virus-induced gene 3 (EBI3) is differentially expressed among BL and DLBCL. Analysis of gene expression data from 502 cases of aggressive mature B-cell lymphomas available on Gene Expression Omnibus and immunohistochemical analysis of 184 cases of BL, BL/DLBCL or DLBCL, showed that EBI3 was not expressed in EBV-positive or -negative BL cases, whereas it was expressed by over 30% of tumoral cells in nearly 80% of DLBCL cases, independently of their subtypes. In addition, we show that c-myc overexpression represses EBI3 expression, and that DLBCL or BL/DLBCL cases with c-myc translocations have lower expression of EBI3. Thus, EBI3 immunohistochemistry could be useful to discriminate BL from DLBCL, and to identify cases of BL/DLBCL or DLBCL with potential c-myc translocations.
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- 2011
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7. The presence of a chromosomal abnormality in cytopenia without dysplasia identifies a category of high‐risk clonal cytopenia of unknown significance
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Victor-Emmanuel, Brett, Nicolas, Lechevalier, Franck, Trimoreau, Charles, Dussiau, Sophie, Dimicoli-Salazar, Lucie, Coster, Isabelle, Luquet, Nathalie, Nadal, Bénédicte, Ribourtout, Elise, Chapiro, Christine, Lefebvre, Sylvie, Tondeur, Estelle, Balducci, Florence, Nguyen-Khac, Claire, Borie, Isabelle, Radford-Weiss, Carole, Barin, Virginie, Eclache, Olivier, Mansier, and Audrey, Bidet
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Chromosome Aberrations ,Cancer Research ,Myelodysplastic Syndromes ,Hematologic Neoplasms ,Mutation ,Genetics ,Humans ,Chromosome Disorders ,Anemia - Abstract
Myelodysplastic syndromes (MDS) are hematological malignancies classically defined by the presence of cytopenia(s) and dysmorphic myeloid cells. It is now known that MDS can be preceded by a pre-malignant condition called clonal cytopenia of unknown significance (CCUS), which associates a clonality marker with cytopenia in the absence of criteria of dysplasia. However, to date, it is not clear whether chromosomal abnormalities should be considered in the definition of CCUS or if they carry a prognostic impact in CCUS patients. In this study, we analyzed the clinico-biological features and outcomes of 34 patients who presented with one or more cytopenias, an absence of significant dysplasia, and a presence of a chromosomal abnormality (CA). We named this entity chromosomal abnormality with cytopenia of undetermined significance (CACtUS). We show that these patients are slightly older than MDS patients and that they more frequently presented with normocytic anemia. Most CACtUS patients exhibited only one unbalanced CA. The number and type of mutations were comparable between CACtUS patients and MDS patients. Regardless of the cytogenetic abnormality, the clinicobiological characteristics, overall survival, and risk of progression to high-risk (HR) MDS were similar between CACtUS patients and low-risk MDS patients. Thus, we suggest that CACtUS patients can be considered as HR-CCUS and should receive the follow-up regimen recommended for MDS patients.
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- 2022
8. RAS activation induces synthetic lethality of MEK inhibition with mitochondrial oxidative metabolism in acute myeloid leukemia
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Justine Decroocq, Rudy Birsen, Camille Montersino, Prasad Chaskar, Jordi Mano, Laury Poulain, Chloe Friedrich, Anne-Sophie Alary, Helene Guermouche, Ambrine Sahal, Guillemette Fouquet, Mathilde Gotanègre, Federico Simonetta, Sarah Mouche, Pierre Gestraud, Auriane Lescure, Elaine Del Nery, Claudie Bosc, Adrien Grenier, Fetta Mazed, Johanna Mondesir, Nicolas Chapuis, Liza Ho, Aicha Boughalem, Marc Lelorc’h, Camille Gobeaux, Michaela Fontenay, Christian Recher, Norbert Vey, Arnaud Guillé, Daniel Birnbaum, Olivier Hermine, Isabelle Radford-Weiss, Petros Tsantoulis, Yves Collette, Rémy Castellano, Jean-Emmanuel Sarry, Eric Pasmant, Didier Bouscary, Olivier Kosmider, Jerome Tamburini, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), 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 Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-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), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Université Paris Cité (UPCité), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Sud Francilien, Laboratorio d'Informatica Musicale (LIM), Università degli Studi di Milano = University of Milan (UNIMI), Institut Curie [Paris], Centre de Bioinformatique (CBIO), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Translational Research Department, Institut Curie, BioImaging Cell and Tissue Core Facility (PICT-IBiSA), Université de Genève = University of Geneva (UNIGE), Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Laboratoire CERBA [Saint Ouen l'Aumône], Département d’Oncologie Médicale [IPC, Marseille], Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Cancer Research and Personalized Medicine - CARPEM [Paris], 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Cochin [AP-HP], and 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)-CHU Necker - Enfants Malades [AP-HP]
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Mitogen-Activated Protein Kinase Kinases ,Cancer Research ,[SDV]Life Sciences [q-bio] ,Hematology ,Proto-Oncogene Proteins p21(ras) ,Leukemia, Myeloid, Acute ,Mice ,Oxidative Stress ,fms-Like Tyrosine Kinase 3 ,Oncology ,hemic and lymphatic diseases ,Mutation ,Animals ,Humans ,Synthetic Lethal Mutations ,neoplasms - Abstract
Despite recent advances in acute myeloid leukemia (AML) molecular characterization and targeted therapies, a majority of AML cases still lack therapeutically actionable targets. In 127 AML cases with unmet therapeutic needs, as defined by the exclusion of ELN favorable cases and of FLT3-ITD mutations, we identified 51 (40%) cases with alterations in RAS pathway genes (RAS+, mostly NF1, NRAS, KRAS, and PTPN11 genes). In 79 homogeneously treated AML patients from this cohort, RAS+ status were associated with higher white blood cell count, higher LDH, and reduced survival. In AML models of oncogenic addiction to RAS-MEK signaling, the MEK inhibitor trametinib demonstrated antileukemic activity in vitro and in vivo. However, the efficacy of trametinib was heterogeneous in ex vivo cultures of primary RAS+ AML patient specimens. From repurposing drug screens in RAS-activated AML cells, we identified pyrvinium pamoate, an anti-helminthic agent efficiently inhibiting the growth of RAS+ primary AML cells ex vivo, preferentially in trametinib-resistant PTPN11- or KRAS-mutated samples. Metabolic and genetic complementarity between trametinib and pyrvinium pamoate translated into anti-AML synergy in vitro. Moreover, this combination inhibited the propagation of RA+ AML cells in vivo in mice, indicating a potential for future clinical development of this strategy in AML.
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- 2022
9. The CADM1 tumor suppressor gene is a major candidate gene in MDS with deletion of the long arm of chromosome 11
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Virginie Eclache, John Boudjarane, Naïs Prade, Stéphanie Struski, Laetitia Largeaud, Cyril Broccardo, Joop H. Jansen, Christine Terré, Marie-Agnès Collonge-Rame, Pierre-Yves Juvin, Dominique Penther, Stéphanie Lagarde, Antoine Ittel, Véronique Mansat-De Mas, G Ameye, Isabelle Luquet, Marina Lafage-Pochitaloff, Carole Barin, David Rombaut, Bastien Gerby, Carine Gervais, Steven Richebourg, Oliver M. Dovey, Pierre Bories, Christine Lefebvre, Isabelle Radford-Weiss, Audrey Bidet, Isabelle Tigaud, George S. Vassiliou, Benedicte Ribourtout, Tobias Tekath, Michaela Fontenay, Lucienne Michaux, Sylvie Hébrard, Hélène Antoine-Poirel, Laura Jamrog, Vincent Fregona, Nathalie Nadal, Eric Delabesse, Véronique Baccini, Kosuke Yusa, Gerby, Bastien [0000-0002-2657-4200], Baccini, Véronique [0000-0003-3913-7664], Largeaud, Laetitia [0000-0001-5341-5427], Fregona, Vincent [0000-0003-4857-1737], Prade, Naïs [0000-0003-4718-7848], Jamrog, Laura [0000-0003-2288-0806], Mansat-De Mas, Véronique [0000-0003-1878-9129], Dovey, Oliver M [0000-0003-3586-4813], Yusa, Kosuke [0000-0002-3442-021X], Vassiliou, George S [0000-0003-4337-8022], Jansen, Joop H [0000-0001-9459-568X], Tekath, Tobias [0000-0002-9315-5452], Rombaut, David [0000-0001-8910-0945], Ameye, Geneviève [0000-0002-5838-2879], Ittel, Antoine [0000-0001-5067-575X], Michaux, Lucienne [0000-0002-8357-7942], Poirel, Hélène A [0000-0002-0712-5127], Struski, Stéphanie [0000-0002-2282-4364], Fontenay, Michaela [0000-0002-5492-6349], Broccardo, Cyril [0000-0003-3016-6549], Delabesse, Eric [0000-0002-0928-0753], Apollo - University of Cambridge Repository, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), and 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)
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INVOLVEMENT ,Candidate gene ,Myeloid ,Tumor suppressor gene ,SCORING SYSTEM ,[SDV]Life Sciences [q-bio] ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Biology ,CLASSIFICATION ,03 medical and health sciences ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Genes, Tumor Suppressor ,TSLC1/IGSF4 ,030304 developmental biology ,MYELODYSPLASTIC SYNDROME ,0303 health sciences ,Science & Technology ,Myeloid Neoplasia ,Myelodysplastic syndromes ,MALE-INFERTILITY ,Chromosomes, Human, Pair 11 ,TSLC1 ,Cell Adhesion Molecule-1 ,Myeloid leukemia ,KARYOTYPE ,Hematology ,medicine.disease ,3. Good health ,Transplantation ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,KMT2A ,030220 oncology & carcinogenesis ,CELL-ADHESION MOLECULE ,Myelodysplastic Syndromes ,Cancer research ,biology.protein ,Female ,Bone marrow ,Chromosome Deletion ,Life Sciences & Biomedicine ,LEUKEMIA - Abstract
Key Points We detail at clinical, cytological, cytogenetic, and molecular levels 113 cases of MDS and MDS/MPN with del(11q), a rare recurrent event.CADM1, a tumor suppressor gene identified initially in solid tumors, ATM, CBL, and KMT2A are deleted and/or mutated in del(11q)., Visual Abstract, Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic, and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count, and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A, and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as Tumor Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid-to-myeloid ratio in bone marrow, although not altering their multilineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM, and CBL and mutations of ASXL1, SF3B1, and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies.
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- 2022
10. Acquired Spherocytosis Due to Somatic ANK1 Mutations as a Manifestation of Clonal Hematopoiesis in Elderly Patients
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Lamisse Mansour‐Hendili, Edouard Flamarion, Marc Michel, Caroline Morbieu, Christine Gameiro, Ivan Sloma, Bouchra Badaoui, Luc Darnige, Marion Camard, Ariane Lunati‐Rozie, Abdelrazak Aissat, Sihem Tarfi, Chloé Friedrich, Véronique Picard, Loïc Garçon, Nasséra Abermil, Sophie Kaltenbach, Isabelle Radford‐Weiss, Olivier Kosmider, Pascale Fanen, Pablo Bartolucci, Bertrand Godeau, Frédéric Galactéros, Benoît Funalot, Hôpital Henri Mondor, 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), CHU Henri Mondor, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre National de Référence Maladies auto-immunes Systémiques Rares [CHU Pitié-Salpêtrière], Service de Département de médecine interne et immunologie clinique [CHU Pitié-Salpêtrière] (DMIIC), 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 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), Génétique Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Laboratoire d'Hématologie et d'Immunologie [CHU Henri Mondor], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), GHU AP-HP Centre Université de Paris, Université Paris Cité (UPCité), Innovations thérapeutiques en hémostase (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Laboratoire d'Hématologie [CHU Amiens], CHU Amiens-Picardie, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'Hématologie et d'Immunologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immunologie et hématologies biologiques [CHU Saint-Antoine], Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Université Sorbonne Paris Cité (USPC), IMRB - GEIC2O/'Genetic and Environmental Interactions in COPD, Cystic fibrosis and Other (rare) respiratory diseases' [Créteil] (U955 Inserm - UPEC), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), IMRB - 'Transfusion et Maladies du Globule Rouge' [Créteil] (U955 Inserm - UPEC), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Unité des Maladies Génétiques du Globule Rouge [CHU Mondor], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
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Ankyrins ,Mutation ,Humans ,Spherocytosis, Hereditary ,Hematology ,Clonal Hematopoiesis ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Aged ,Hematopoiesis - Abstract
International audience
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- 2022
11. Somatic genetic rescue of a germline ribosome assembly defect
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Vasileios Kargas, Mélanie Parisot, Norberto Escudero-Urquijo, Alexis Bertrand, Christine Bellanné-Chantelot, Jean Donadieu, Mohammed Zarhrate, Patrick Nitschke, Cécile Masson, Laëtitia Kermasson, Beatriz Goyenechea, Sophie Kaltenbach, Alan J. Warren, David Traynor, Stefano Fumagalli, Li Jin, Blandine Beaupain, Bruno Reversade, Ahmed Z. Boukerrou, Peter J. Bond, M. Rossmann, Olivier Alibeu, Jean-Alain Martignoles, Christine Bole-Feysot, Jonathan Moreil, Shengjiang Tan, François Delhommeau, Patrick Revy, Kong Boo Phua, Alexandre Faille, Aurore Pouliet, Christine Hilcenko, Frédéric Tores, Isabelle Radford-Weiss, Ai Ling Koh, Isabelle Callebaut, Jean-Pierre de Villartay, Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), MRC Laboratory of Molecular Biology [Cambridge, UK] (LMB), University of Cambridge [UK] (CAM)-Medical Research Council, Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), CHU Trousseau [APHP], 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), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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), KK Women's and Children's Hospital [Singapore], Genome Institute of Singapore (GIS), Bioinformatics Institute [Singapore], Agency for science, technology and research [Singapore] (A*STAR), National University of Singapore (NUS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Babraham Research Campus [Cambridge, Royaume-Uni], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), Université Sorbonne Paris Cité (USPC), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ACS - Heart failure & arrhythmias, ARD - Amsterdam Reproduction and Development, Escudero-Urquijo, Norberto [0000-0002-8201-5884], Parisot, Mélanie [0000-0003-4312-2035], Reversade, Bruno [0000-0002-4070-7997], Bond, Peter J. [0000-0003-2900-098X], Bellanné-Chantelot, Christine [0000-0001-8415-6771], Warren, Alan J. [0000-0001-9277-4553], Revy, Patrick [0000-0003-0758-8022], Apollo - University of Cambridge Repository, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Hilcenko, Christine [0000-0002-9596-7833], Rossmann, Maxim [0000-0001-8811-3277], Bond, Peter J [0000-0003-2900-098X], Warren, Alan [0000-0001-9277-4553], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), HAL-SU, Gestionnaire, ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Warren, Alan J [0000-0001-9277-4553]
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Somatic cell ,[SDV]Life Sciences [q-bio] ,General Physics and Astronomy ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,Germline ,631/208/737 ,692/699/1541 ,Ribosome assembly ,13/1 ,0302 clinical medicine ,hemic and lymphatic diseases ,38/22 ,Dictyostelium ,Eukaryotic Initiation Factors ,Child ,Cells, Cultured ,Biological Phenomena ,Genetics ,0303 health sciences ,Multidisciplinary ,631/208/514/2254 ,article ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,Ribosome Subunits, Large, Eukaryotic ,Ribosome ,Shwachman-Diamond Syndrome ,3. Good health ,[SDV] Life Sciences [q-bio] ,64/24 ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,030220 oncology & carcinogenesis ,Child, Preschool ,Drosophila ,Haematological diseases ,Protein Binding ,Adult ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,Science ,45/23 ,Saccharomyces cerevisiae ,Biology ,Molecular Dynamics Simulation ,General Biochemistry, Genetics and Molecular Biology ,82/80 ,03 medical and health sciences ,Young Adult ,Germline mutation ,Animals ,Humans ,Gene ,Ribonucleoprotein, U5 Small Nuclear ,030304 developmental biology ,Sequence Homology, Amino Acid ,Eukaryotic Large Ribosomal Subunit ,Point mutation ,Infant ,Proteins ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,General Chemistry ,SBDS ,96/44 ,Peptide Elongation Factors ,Germ Cells ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Protein Biosynthesis ,Mutation ,Next-generation sequencing ,631/337/574/1789 ,Ribosomes - Abstract
Indirect somatic genetic rescue (SGR) of a germline mutation is thought to be rare in inherited Mendelian disorders. Here, we establish that acquired mutations in the EIF6 gene are a frequent mechanism of SGR in Shwachman-Diamond syndrome (SDS), a leukemia predisposition disorder caused by a germline defect in ribosome assembly. Biallelic mutations in the SBDS or EFL1 genes in SDS impair release of the anti-association factor eIF6 from the 60S ribosomal subunit, a key step in the translational activation of ribosomes. Here, we identify diverse mosaic somatic genetic events (point mutations, interstitial deletion, reciprocal chromosomal translocation) in SDS hematopoietic cells that reduce eIF6 expression or disrupt its interaction with the 60S subunit, thereby conferring a selective advantage over non-modified cells. SDS-related somatic EIF6 missense mutations that reduce eIF6 dosage or eIF6 binding to the 60S subunit suppress the defects in ribosome assembly and protein synthesis across multiple SBDS-deficient species including yeast, Dictyostelium and Drosophila. Our data suggest that SGR is a universal phenomenon that may influence the clinical evolution of diverse Mendelian disorders and support eIF6 suppressor mimics as a therapeutic strategy in SDS., Shwachman-Diamond syndrome (SDS) is a leukemia predisposition disorder that is caused by defective release of eIF6 during ribosome assembly. Here the authors show that acquired somatic EIF6 mutations are frequent in the hematopoietic cells from individuals with SDS and provide a selective advantage over non-modified cells.
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- 2021
12. Battle of the clones: paroxysmal nocturnal hemoglobinuria vs myelodysplastic syndrome
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Chloé Friedrich, Juliette Gay, Anne-Sophie Alary, Jean-Benoît Arlet, Gérard Socie, Véronique Fremaux-Bacchi, Isabelle Radford Weiss, Olivier Kosmider, and Luc Darnige
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medicine.medical_specialty ,Erythrocyte transfusion ,Hematology ,biology ,business.industry ,General Medicine ,medicine.disease ,Gastroenterology ,Remission induction ,Internal medicine ,Monoclonal ,medicine ,biology.protein ,Paroxysmal nocturnal hemoglobinuria ,Combined Modality Therapy ,Hemoglobinuria ,Antibody ,business - Published
- 2020
13. The fraction of CD117/c‐KIT‐expressing erythroid precursors predicts ESA response in low‐risk myelodysplastic syndromes
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Sylvain Clauser, Stéphanie Mathis, Didier Bouscary, Raphael Itzykson, Nicolas Chapuis, Valérie Bardet, Anna Raimbault, Alice Rousseau, Michaela Fontenay, Lise Willems, Isabelle Radford-Weiss, and Olivier Kosmider
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Male ,Risk ,0301 basic medicine ,Histology ,Primary Cell Culture ,Gene Expression ,Context (language use) ,Theranostic Nanomedicine ,Pathology and Forensic Medicine ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Erythropoiesis ,Prospective Studies ,Erythropoietin ,Erythroid Precursor Cells ,Red Cell ,medicine.diagnostic_test ,biology ,business.industry ,CD117 ,Myelodysplastic syndromes ,Cell Biology ,Prognosis ,medicine.disease ,Progression-Free Survival ,digestive system diseases ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,Cell culture ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Hematinics ,Cancer research ,biology.protein ,Female ,business ,Cytometry ,Biomarkers ,medicine.drug - Abstract
Background Compelling evidence has emerged for the relevance of flow cytometry (FC) in the diagnostic work-up of myelodysplastic syndromes (MDS) but due to technical issues, the erythroid lineage has been under investigated, specifically in the therapeutic context. Methods Using the "no red cell lysis" method developed to set up the RED-score, we specifically quantified the fraction of CD117/c-KIT-expressing erythroid precursors in a cohort of 144 MDS patients and studied the correlation with response to erythropoiesis-stimulating agents (ESA) in a sub cohort of 63 low-risk MDS patients. Results We confirmed the previously reported increase in CD117/c-KIT-expressing erythroid precursors in a subset of MDS patients and demonstrated a strong association between a cut off of CD117/c-KIT-expressing erythroid precursors ≥3% and ESA response (P = 0.001), independent of red blood cell requirement. From our observations, we hypothesized that a decrease in CD117/c-KIT-expressing erythroid precursors could be a mechanism of ESA failure. Moreover, the fraction of CD117/c-KIT-expressing erythroid precursors was correlated with progression-free survival in low-risk MDS patients (P = 0.018). In vitro, we demonstrated in an EPO dependent cell line that CD117/c-KIT expression is necessary for cell survival under EPO stimulation. Conclusions The quantification of the CD117/c-KIT-expressing erythroid precursors could be proposed as a new theranostic and prognostic marker in MDS treated by ESA. Future studies will be required to determine whether modulating CD117/c-KIT expression and signaling could be used to improve anemia in MDS. © 2019 International Clinical Cytometry Society.
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- 2019
14. Successful in utero stem cell transplantation in X-linked severe combined immunodeficiency
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Aurélie Gabrion, Elisabeth A. Macintyre, Emmanuel Clave, Anne-Marie Darras, Alessandra Magnani, Stéphane Blanche, Brigitte Ternaux, Antoine Toubert, Capucine Picard, Marina Cavazzana, Cécile Roudaut, Laure Caccavelli, Jérémie Rosain, Elisa Magrin, Nizar Mahlaoui, Jennifer Nisoy, Fabien Touzot, Marion Alcantara, Isabelle Radford-Weiss, Jean-Marie Jouannic, Sven Kracker, 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), Centre pluridisciplinaire de diagnostic prénatal [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], CHU Necker - Enfants Malades [AP-HP], Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-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'Immunologie et d'Histocompatibilité, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm 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)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), 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)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], 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), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP]
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Transplantation Conditioning ,[SDV]Life Sciences [q-bio] ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,X-Linked Combined Immunodeficiency Diseases ,Bioinformatics ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Humans ,X-linked severe combined immunodeficiency ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,Severe combined immunodeficiency ,business.industry ,Hematopoietic Stem Cell Transplantation ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,Hematology ,medicine.disease ,Stimulus Report ,3. Good health ,Transplantation ,medicine.anatomical_structure ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,In utero ,Child, Preschool ,030220 oncology & carcinogenesis ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,Bone marrow ,Stem cell ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Key Points IUT enables rapid immune reconstitution and avoids many clinical and economic problems; however, the indication is still limited. IUT may be a treatment option in select cases, eg, fetuses exposed to a significant infectious risk, where a matched sibling donor exists.
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- 2019
15. Improvement of therapy-induced myelodysplastic syndrome by infusion of autologous CD34-positive hematopoietic progenitor cells without chemotherapy
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Nicolas Chapuis, Raphael Carapito, Seiamak Bahram, Farhad Heshmati, Lise Willems, Isabelle Radford-Weiss, Marguerite Vignon, Olivier Kosmider, Jerome Tamburini, Didier Bouscary, Wendy Cuccuini, Alexa Green, Anne-Sophie Alary, Arash Rafii, Najeeb Halabi, Sophie Kaltenbach, Immuno-Rhumatologie Moléculaire, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)
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Oncology ,Melphalan ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,CD34 ,Antigens, CD34 ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Hematopoietic stem cell transplantation ,Transplantation, Autologous ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Multiple myeloma ,Chemotherapy ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,medicine.disease ,Hematopoietic Stem Cells ,3. Good health ,Transplantation ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,Hematopoietic progenitor cells ,business ,030215 immunology ,medicine.drug - Abstract
Recent years have witnessed a dramatic improvement in multiple myeloma (MM) patient care with a current median life expectancy of 6 to 10 years dependent on age. High-dose melphalan followed by aut...
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- 2020
16. Hemolytic anemia, iron deficiency and personal history of deep vein thrombosis: consider paroxysmal nocturnal hemoglobinuria
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Régis Peffault de La Tour, Luc Darnige, Pascale Gaussem, Sidonie Dupeux, Jean-Benoît Arlet, Nicolas Gendron, Jérémie Rosain, and Isabelle Radford-Weiss
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Male ,Hemolytic anemia ,Anemia, Hemolytic ,medicine.medical_specialty ,Anemia ,Urinary system ,Deep vein ,Hemoglobinuria, Paroxysmal ,01 natural sciences ,Gastroenterology ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,0101 mathematics ,Aged ,Venous Thrombosis ,Anemia, Iron-Deficiency ,business.industry ,010102 general mathematics ,Hematopoietic stem cell ,General Medicine ,Hematology ,Iron deficiency ,medicine.disease ,Thrombosis ,Hemolysis ,medicine.anatomical_structure ,Paroxysmal nocturnal hemoglobinuria ,business - Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hematopoietic stem cell disorder that must be correctly diagnose because it is a chronic disease with a real impact on the quality of life and the survival of the patients. PNH screening of all patients with anemia or thrombosis is not recommended. We report the case of a 71-year-old male patient referred for chronic anemia. Anemia work-up revealed a misunderstood association of a hemolytic anemia with a negative direct antiglobulin test and iron deficiency. The patient exhibits biological signs of intravascular hemolysis, as well as a recent history of two episodes of deep vein thrombosis. Screening for PNH by flow cytometry shown a PNH clone with a size of approximately 33% of the granulocytes and 11% of the red blood cells. An interstitial deletion of the chromosome 13 was found in the medullar karyotype. PNH through chronic intravascular hemolysis induces an urinary iron loss. This is the only cause of hemolytic anemia inducing iron deficiency.
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- 2018
17. Genetic characterization of B-cell prolymphocytic leukemia: a prognostic model involving MYC and TP53
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Olivier A. Bernard, Elodie Pramil, Florence Nguyen-Khac, Clementine Gabillaud, Nathalie Nadal, Elise Chapiro, Simon Bouzy, Frederic Davi, Stéphanie Struski, Damien Roos-Weil, Christine Lefebvre, Evelyne Callet-Bauchu, Magali Le Garff-Tavernier, Philippe Dessen, Virginie Eclache, Caroline Algrin, Jean-François Lesesve, Veronique Leblond, Lena Wagner, Claude Lesty, Sandra Fert-Ferrer, Melanie Yon, Ludovic Jondreville, Nathalie Auger, Jean Gabarre, Antoine Ittel, Marie-Agnès Collonge-Rame, Karim Maloum, Clémentine Dillard, M'Boyba Diop, Catherine Settegrana, Thorsten Zenz, Sebastian Scheinost, Baptiste Gaillard, Benoit Quilichini, Isabelle Radford-Weiss, Marc Muller, Nathalie Droin, Lucile Baseggio, Santos A. Susin, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Institut Gustave Roussy (IGR), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hospices Civils de Lyon (HCL), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), 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)-Sorbonne Université (SU), Hématopoïèse normale et pathologique (U1170 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Hôpital Robert Debré, Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Strasbourg, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), CHU Toulouse [Toulouse]-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 Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Métropole Savoie [Chambéry], CHU Necker - Enfants Malades [AP-HP], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Universität Zürich [Zürich] = University of Zurich (UZH), Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-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], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Hospitalier Mutualiste [Grenoble] (GHM), Hôpital Avicenne [AP-HP], Service d'hématologie [Reims], Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Service de Génétique [CHRU Nancy], 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), Eurofins Biomnis, Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], and University hospital of Zurich [Zurich]
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0301 basic medicine ,Male ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,Immunology ,Chromosomal translocation ,Biology ,Biochemistry ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,0302 clinical medicine ,SETD2 ,B-cell prolymphocytic leukemia ,medicine ,Humans ,Prolymphocytic leukemia ,Aged ,Aged, 80 and over ,Chromosome Aberrations ,Leukemia, Prolymphocytic, B-Cell ,Cytogenetics ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,3. Good health ,Leukemia ,030104 developmental biology ,Cytogenetic Analysis ,Chromosome abnormality ,Cancer research ,Female ,Tumor Suppressor Protein p53 ,IGHV@ ,030215 immunology - Abstract
International audience; B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessment of 34 patients with B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex ({greater than or equal to}3 abnormalities) in 73% of the patients and highly complex (>5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving MYC [t(MYC)] (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six of the 34 patients (76%) exhibit MYC aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1 The majority of B-PLL used the IGHV3 or IGHV4 subgroups (89%), and displayed significantly mutated IGHV genes (79%). We identified three distinct cytogenetic risk groups: low-risk (no MYC aberration), intermediate-risk (MYC aberration but no del17p), and high-risk (MYC aberration and del17p) (p=.0006). In vitro drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif (BET) inhibitor targeting MYC) was associated with significantly lower viability of B-PLL cells harboring a t(MYC). We conclude that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting MYC may be a useful treatment option in this disease.
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- 2019
18. Early thymic precursor-like lymphomatous presentation of theETV6-NCOA2translocation
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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
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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
19. Combination of the MEK Inhibitor Trametinib and Pyrvinium Pamoate Efficiently Targets RAS Pathway-Mutated Acute Myeloid Leukemia in Preclinical Models
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Isabelle Radford-Weiss, Jordi Mano, Sarah Mouche, Adrien Grenier, Jerome Tamburini, Aicha Boughalem, Ivan C. Moura, Justine Decroocq, Rudy Birsen, Guillemette Fouquet, Didier Bouscary, Marc Le Lorc'h, Fetta Mazed, Anne-Sophie Alary, Olivier Hermine, Laury Poulain, Eric Pasmant, Johanna Mondesir, Nicolas Chapuis, Mathilde Gotanègre, Jean-Emmanuel Sarry, and Olivier Kosmider
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Trametinib ,business.industry ,MEK inhibitor ,Immunology ,Myeloid leukemia ,Cancer ,Cell Biology ,Hematology ,medicine.disease ,Oncogene Addiction ,medicine.disease_cause ,Biochemistry ,Leukemia ,medicine ,Cancer research ,Pharmaceutical sciences ,business ,Carcinogenesis - Abstract
While acute myeloid leukemia (AML) is still associated with a low cure rate, recent advances in understanding its molecular complexity have significantly improved therapy for subgroups of patients, including those harboring FLT3, IDH1 or IDH2 mutations1. However, more than half of AML cases still lack a druggable oncogenic target. Human cancers frequently harbor mutations in RAS oncogene family members, including NRAS, KRAS and HRAS, which drive oncogenesis by augmenting cellular proliferation and survival. These are small protein GTPases, regulated by a switch between active GTP-linked and inactive GDP-bound states governed by a complex network of guanine exchange factors (GEFs, favoring RAS-GTP) and GTPase activating factors (GAPs, favoring RAS-GDP). RAS activation - due to either extrinsic recruitment by transmembrane tyrosine kinase receptors or intrinsic mutations - propagates through the downstream RAF/MEK/ERK and PI3K/AKT signaling pathways. Besides RAS-activating mutations conferring independence from physiological regulators, human cancers harbor mutations in other RAS network genes such as NF1 (encoding neurofibromin, a RAS GAP), BRAF or PTPN11 (encoding the SHP2 tyrosine phosphatase involved in RAS activation). Somatic alterations of RAS pathway genes, notably NRAS, KRAS, PTPN11 (missense mutations) and NF1 (mutations and deletions), are reported in up to 20% of AML cases2. Generally arising as late driver events, RAS pathway mutations participate in leukemogenesis through mitogen activated protein kinase (MAPK) activation. The anti-tumor activity of MEK inhibitors in Nras-mutated AML in mice and in some NRAS or KRAS-mutated AML patients suggests that deregulated RAS pathway signaling may represent a bona fide therapeutic target. However, strategies to inhibit RAS - indirectly in most cases - have been hampered by signaling feedback, redundancy and tumor heterogeneity 3. We identified 127 cases of AML with unmet therapeutic need within a cohort from which we excluded those with European leukemia network (ELN) favorable prognosis or FLT3-ITD mutations. Targeted next-generation sequencing revealed RAS pathway alterations in 50 patients (39.3%) and NF1 mutations and deletions, mostly large cytogenetically detected deletions, in 17 (14.8%). NRAS, KRAS, PTPN11, CBL and BRAF variants were detected in 13 (10.4%), 10 (7.9%), 9 (7.2%), 5 (3.9%) and 2 (1.6%) cases, respectively. Mutations in RAF1, RASA1, SOS1 and MAP2K2 were observed in a single case each. RAS pathway alterations appeared in the putative main leukemic clone as well as in subclones inferred from variant allele frequencies. Concurrent RAS pathway mutations were observed in nine cases. Among 79 patients homogeneously treated with intensive induction chemotherapy, RAS pathway alterations correlated with higher clinical proliferation markers (elevated white blood cell count, blast cell percentage and LDH levels) and reduced survival probability, particularly within the ELN intermediate-risk subgroup. We established robust models of RAS/MAPK activation through genetic NF1 disruption or expression of NRASG12D or PTPN11D61Y in growth factor (GF)-dependent cell lines. We assessed oncogenic addiction to the RAS pathway in these cells through GF-independence, increased RAS activity, faster propagation in immunocompromised mice and an exquisite sensitivity to pharmacological MEK inhibition in vitro and in vivo. High-content pharmacological screens with FDA-approved molecules identified pyrvinium pamoate, an anti-helminthic agent, as preferentially active in RAS-activated cells. This compound significantly impaired cell viability and colony formation in primary AML samples with RAS pathway alterations. Moreover, the combination of trametinib and pyrvinium pamoate demonstrated synergy in cell line models and even primary samples. While pyrvinium pamoate strongly inhibited mitochondrial respiration and induced metabolic reprograming towards increased glycolysis, trametinib impaired glycolysis and mitochondrial respiratory capacity, suggesting a mechanistic basis for the synergy observed. These data highlight the translational opportunity in developing pyrvinium pamoate for RAS pathway mutated AML. References 1. Raj RV et al. Leuk. Res. 2018;74:113-120. 2. Simanshu DK et al. Cell. 2017;170(1):17-33. 3.Ryan MB et al. Nat Rev Clin Oncol. 2018;15(11):709-720. Figure Disclosures Hermine: AB Science: Membership on an entity's Board of Directors or advisory committees. Tamburini:Novartis pharmaceutical: Research Funding; Incyte: Research Funding.
- Published
- 2019
20. PB1868 B-CELL PROLYMPHOCYTIC LEUKEMIA (B-PLL) AND PROLYMPHOCYTOID MANTLE CELL LYMPHOMA (PMCL) (MORE THAN 55% OF PROLYMPHOCYTES) ARE CLOSED BUT DISTINCT ENTITIES. ON BEHALF GFCH AND FILO GROUPS
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Frederic Davi, Caroline Algrin, Clementine Gabillaud, Nathalie Nadal, Philippe Dessen, Baptiste Gaillard, L. Baseggio, Sandra Fert-Ferrer, K. Diop, Isabelle Radford-Weiss, Marc Muller, Nathalie Auger, Benoit Quilichini, M Le Garff-Tavernier, Virginie Eclache, Evelyne Callet-Bauchu, Christine Lefebvre, Elodie Pramil, Nathalie Droin, Olivier Bernard, Damien Roos-Weil, Elise Chapiro, Stéphanie Struski, Florence Nguyen-Khac, Antoine Ittel, Catherine Settegrana, Marie-Agnès Collonge-Rame, Karim Maloum, Santos A. Susin, and Veronique Leblond
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B-cell prolymphocytic leukemia ,medicine ,Cancer research ,Mantle cell lymphoma ,Hematology ,Biology ,medicine.disease - Published
- 2019
21. Technique d’immunofluorescence et FISH combinées sur tissu fixé en formol et inclus en paraffine : application au lymphome de Hodgkin
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Isabelle Radford-Weiss, Sophie Kaltenbach, Christophe Bontoux, and Serge Romana
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0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Anatomy - Abstract
Introduction/objectifs Le lymphome de Hodgkin classique (LHc) presente une histologie particuliere caracterisee par peu de cellules tumorales CD30+ [1] . Le LHc exploite la voie PD1/PDL1 via une alteration du nombre de copie du gene CD274/PDL1 (9p24,1) codant pour PDL1 et represente donc un excellent candidat aux therapies anti-PD1 [2] , [3] . L’amplification CD274/PDL1 pourrait avoir un role pronostique [4] . L’objectif est de developper une technique d’immunofluorescence-FISH combinee CD30/PDL1 pour reperer les cellules tumorales et ainsi ameliorer la detection des anomalies cytogenetiques de CD274/PDL1. Materiels/Patients et methodes L’immunofluorescence-FISH est realisee sur prelevements fixes en formol et inclus en paraffine. Apres deparaffinage, le demasquage antigenique est realise dans un tampon pH6 a 99 °C. L’anticorps primaire et l’anticorps secondaire fluorescent rouge sont incubes sequentiellement pendant 1 h. La sonde « maison » PDL1 est ensuite appliquee. Le lavage post-hybridation est realise dans du PBS/0,1 % Tween20. Deux cas sont analyses et 50 cellules tumorales sont comptees a l’aide d’un microscope a epifluorescence. Resultats On observe la presence d’anomalies recurrentes et heterogenes du gene CD274/PDL1 dans les cellules tumorales marquees par l’anticorps fluorescent rouge anti-CD30. Le premier cas montre 68 % de cellules presentant un « gain » PDL1, 22 % une « amplification », 6 % une polysomie du chromosome 9 et 2 % sans anomalie. Le second patient montre 64 % de cellules tumorales avec une « amplification » PDL1, 30 % avec un « gain » et 6 % sans anomalie. Par rapport a une FISH classique, Il faut 3 h supplementaires de technique correspondant a l’etape d’immunofluorescence CD30. Le temps d’analyse est d’environ 1 h. Conclusions Cette technique est realisable dans la plupart des laboratoires. Elle est applicable a tout les cancers impliquant la voie PD1/PDL1 [5] . Cependant, son interpretation demande un temps d’analyse consequent, plus adapte a de la recherche. Des etudes sur de plus grandes series de patients sont necessaires pour juger de son utilite.
- Published
- 2018
22. Genetic Characterization of B-Cell Prolymphocytic Leukemia (B-PLL): A Hierarchical Prognostic Model Involving MYC and TP53 Abnormalities. on Behalf of the Groupe Francophone De Cytogenetique Hematologique (GFCH) and the French Innovative Leukemia Organization (FILO) Group
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Sandra Fert-Ferrer, Baptiste Gaillard, Nathalie Droin, Lena Wagner, Philippe Dessen, Antoine Ittel, Evelyne Callet-Bauchu, Catherine Settegrana, Benoit Quilichini, Nathalie Auger, Virginie Eclache, Melanie Yon, Nadia Bougacha, Karim Maloum, Florence Nguyen-Khac, Elodie Pramil, Elise Chapiro, Christine Lefebvre, Clementine Gabillaud, Nathalie Nadal, Claude Lesty, Frederic Davi, Simon Bouzy, Stéphanie Struski, Damien Roos-Weil, Olivier A. Bernard, Clémentine Dillard, Thorsten Zenz, Santos A. Susin, Marie-Agnès Collonge-Rame, Magali Le Garff-Tavernier, Caroline Algrin, Sebastian Scheinost, M'Boyba Diop, Lucile Baseggio, Isabelle Radford-Weiss, Marc Muller, and Véronique Leblond
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Venetoclax ,business.industry ,Immunology ,Chromosomal translocation ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,03 medical and health sciences ,Leukemia ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,B-cell prolymphocytic leukemia ,Chromosome abnormality ,medicine ,Cancer research ,Mantle cell lymphoma ,Trisomy ,business ,030215 immunology - Abstract
B-PLL is defined by the presence of prolymphocytes in peripheral blood exceeding 55% of lymphoid cells. The diagnosis, mainly based on clinical and morphological data, can be difficult because of overlap with other B-cell malignancies. Because of the rarity of the disease, only case reports and small series describe its cytogenetic features. Few prognostic markers have been identified in this aggressive leukemia usually resistant to standard chemo-immuno therapy. We report here the cytogenetic and molecular findings in a large series of B-PLL. We also studied the in vitro response to novel targeted drugs on primary B-PLL cells. The study included 34 cases with a diagnosis of B-PLL validated by morphological review performed by three independent expert cytologists. The diagnosis of mantle cell lymphoma was excluded by karyotype (K) and FISH using CCND1, CCND2 and CCND3 probes. Median age at diagnosis was 72 years [46-88]. K was complex (≥3 abnormalities) in 73%, and highly complex (HCK≥5) in 45%. Combining K and FISH data, the most frequent chromosomal aberrations were: translocation targeting the MYC gene [t(MYC)] (21/34, 62%), 17p deletion including TP53 gene (13/34, 38%), trisomy 18/18q (10/33, 30%), 13q14 deletion (10/34, 29%), trisomy 3 (8/33, 24%), trisomy 12 (8/34, 24%) and 8p deletion (7/31, 23%). Whole-Exome Sequencing analysis of paired tumor-control DNA was performed in 16 patients. The most frequently mutated genes were TP53(6/16, 38%), associated with del17p in all, MYD88 (n=4), BCOR (n=4), MYC (n=3), SF3B1 (n=3), FAT1 (n=3), SETD2 (n=2), CHD2 (n=2), CXCR4 (n=2), BCLAF1 (n=2) and NFASC (n=2). Distribution of the chromosomal aberrations is shown in Fig 1. The main group of patients (21/34, 62%) had a t(MYC) that was associated with a higher % of prolymphocytes (86 vs 76, p=0.03), CD38 expression (90% vs 15%,p The median overall survival (OS) for the entire cohort was 126 months with a median follow-up time of 47 months [ 0.2-141]. We found MYC activation (translocation or gain) to be associated with a shorter OS (p=0.03). Regarding MYC and del17p, we identified 3 distinct cytogenetic prognostic groups, with significant differences in OS (p=0.0006) (Fig 2). The patients without MYC activation had the lower risk (n=8, median not reached). Patients with a MYC activation without del17p had an intermediate risk (n=18, 125 months). The highest risk group corresponded to patients with both MYC and TP53 aberrations (n=7, 11 months). We performed drug response profiling on primary B-PLL cells using the ATP-based CellTiter Glo kit (Promega) (n=5). We observed that after 48h of exposure to increased doses, response was heterogeneous, with a majority of samples resistant to fludarabine (n=3), ibrutinib (n=3), idelalisib (n=4), venetoclax (n=3) and OTX015 (n=4). Annexin/PI assays using flow cytometry showed that the induced cell death could be increased by combination of ibrutinib or venetoclax with OTX015 or JQ1, two BET protein inhibitors that target MYC signaling (n=1/2). In summary, B-PLL have complex and highly complex K, a high frequency of MYC activation by translocation or gain, frequent 17p deletion, and frequent mutations in MYC, TP53, BCOR, and MYD88 genes. We identified 3 prognostic subgroups according to MYC and 17p status. Patients with MYC activation + 17p deletion have the shorter OS, and should be considered as a high-risk "double-hit" subgroup. Our results show that cytogenetic analysis is a useful diagnostic tool in B-PLL that improves prognostic stratification. We recommend to perform K and FISH (MYC and TP53) analyses systematically when a B-PLL is suspected. Our in vitro data suggest that drugs targeting the BCR and BCL2 in combination with MYC inhibition may be a therapeutic option in some patients. Disclosures Baseggio: Takeda Oncology: Honoraria.
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- 2018
23. Sustained Leukemia-Free State and Molecular Response to Sorafenib in a Patient With Chronic Myelomonocytic Leukemia in Transformation Driven by Homozygous FLT3-ITD Malignant Hematopoiesis
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Virginie Chesnais, Jerome Tamburini, Didier Bouscary, Patrick Mayeux, Pascaline Boudou Rouquette, Sophie Kaltenbach, Olivier Kosmider, Valérie Bardet, Nicolas Chapuis, Lise Willems, Isabelle Radford-Weiss, Michaela Fontenay, and Romain Coriat
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Niacinamide ,Sorafenib ,Cancer Research ,Chronic myelomonocytic leukemia ,Antineoplastic Agents ,medicine ,Humans ,Free state ,business.industry ,Phenylurea Compounds ,Nucleic Acid Hybridization ,Leukemia, Myelomonocytic, Chronic ,Hematology ,Middle Aged ,medicine.disease ,Hematopoiesis ,Haematopoiesis ,Leukemia ,fms-Like Tyrosine Kinase 3 ,Oncology ,Molecular Response ,Cancer research ,business ,medicine.drug ,Flt3 itd - Abstract
Sustained Leukemia-Free State and Molecular Response to Sorafenib in a Patient With Chronic Myelomonocytic Leukemia in Transformation Driven by Homozygous FLT3-ITD Malignant Hematopoiesis Olivier Kosmider, Nicolas Chapuis, Sophie Kaltenbach, Romain Coriat, Pascaline Boudou Rouquette, Lise Willems, Virginie Chesnais, Isabelle Radford-Weiss, Valerie Bardet, Patrick Mayeux, Jerome Tamburini, Michaela Fontenay, Didier Bouscary
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- 2013
24. Chromosomal translocations involving the IGH@ locus in B-cell precursor acute lymphoblastic leukemia: 29 new cases and a review of the literature
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Nicole Dastugue, Carole Barin, Christian Bastard, Olivier A. Bernard, Lisa J. Russell, Stéphanie Struski, Dominique Penther, Nathalie Nadal, Peter Vandenberghe, Isabelle Tigaud, Christine Lefebvre, Elise Chapiro, Florence Nguyen-Khac, Francine Mugneret, Marie-Joelle Mozziconacci, Christine J. Harrison, Eric Lippert, Pascaline Talmant, Sylvie Taviaux, Isabelle Radford-Weiss, Serge Romana, and Hong-Anh Cung
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Adult ,Male ,Cancer Research ,Adolescent ,Chromosomal translocation ,Biology ,Molecular cloning ,Real-Time Polymerase Chain Reaction ,Translocation, Genetic ,hemic and lymphatic diseases ,Receptors, Erythropoietin ,Genetics ,medicine ,Humans ,Gene family ,Cloning, Molecular ,Child ,Molecular Biology ,Gene ,In Situ Hybridization, Fluorescence ,B cell ,Aged ,Aged, 80 and over ,Chromosomes, Human, Pair 14 ,medicine.diagnostic_test ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Real-time polymerase chain reaction ,medicine.anatomical_structure ,Proto-Oncogene Proteins c-bcl-2 ,Child, Preschool ,CCAAT-Enhancer-Binding Proteins ,Immunoglobulin heavy chain ,Female ,Inhibitor of Differentiation Proteins ,Immunoglobulin Heavy Chains ,Fluorescence in situ hybridization - Abstract
Chromosomal translocations involving the immunoglobulin heavy chain locus (IGH@) are recurrent but rare in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), and various partner genes have been described. Here, we report a new series of 29 cases of BCP-ALL with IGH@ translocations. The partner gene was identified by fluorescence in situ hybridization and/or molecular cloning in 20 patients. Members of the CEBP gene family (n = 11), BCL2 (n = 3), ID4 (n = 3), EPOR (n = 2), and TRA/D@ (n = 1) were identified and demonstrated by quantitative real-time reverse transcriptase-polymerase chain reaction to be markedly up-regulated. The present cases, added to those already reported, confirm the diversity of the partner genes, which, apart from BCL2, are specific to BCP-ALL. Collectively, patients with IGH@ translocations may represent a novel sub-group of BCP-ALL occurring in adolescents and young adults.
- Published
- 2013
25. Formation of Nup98-containing nuclear bodies in HeLa sublines is linked to genomic rearrangements affecting chromosome 11
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Marie-Claude Geoffroy, Jean-Michel Lapierre, Valérie Doye, Serge Romana, Isabelle Radford-Weiss, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (UMR_S_944)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service de Cytogénétique, Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Université Sorbonne Paris Cité ( USPC ), Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre national de la recherche scientifique (CNRS), Fondation ARC pour la Recherche sur le Cancer ('Programme ARC), Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Université Sorbonne Paris Cité (USPC), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
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0301 basic medicine ,Repetitive Sequences, Amino Acid ,[SDV]Life Sciences [q-bio] ,Chromosomal translocation ,Translocation, Genetic ,HeLa ,03 medical and health sciences ,Rapid amplification of cDNA ends ,Cell Line, Tumor ,Genetics ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Nuclear pore ,Nucleoporin ,[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Genetics (clinical) ,In Situ Hybridization, Fluorescence ,ComputingMilieux_MISCELLANEOUS ,Comparative Genomic Hybridization ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Leukemia ,biology ,Chromosomes, Human, Pair 11 ,Gene Amplification ,Chromosome ,Hep G2 Cells ,Nup98 Leukaemia ,biology.organism_classification ,Molecular biology ,Homogeneously staining region ,Nuclear Pore Complex Proteins ,030104 developmental biology ,Chromosome 3 ,Caco-2 Cells ,[ SDV.GEN ] Life Sciences [q-bio]/Genetics ,Developmental biology ,HeLa Cells - Abstract
Nup98 is an important component of the nuclear pore complex (NPC) and also a rare but recurrent target for chromosomal translocation in leukaemogenesis. Nup98 contains multiple cohesive Gly-Leu-Phe-Gly (GLFG) repeats that are critical notably for the formation of intranuclear GLFG bodies. Previous studies have reported the existence of GLFG bodies in cells overexpressing exogenous Nup98 or in a HeLa subline (HeLa-C) expressing an unusual elevated amount of endogenous Nup98. Here, we have analysed the presence of Nup98-containing bodies in several human cell lines. We found that HEp-2, another HeLa subline, contains GLFG bodies that are distinct from those identified in HeLa-C. Rapid amplification of cDNA ends (RACE) revealed that HEp-2 cells express additional truncated forms of Nup98 fused to a non-coding region of chromosome 11q22.1. Cytogenetic analyses using FISH and array-CGH further revealed chromosomal rearrangements that were distinct from those observed in leukaemic cells. Indeed, HEp-2 cells feature a massive amplification of juxtaposed NUP98 and 11q22.1 loci on a chromosome marker derived from chromosome 3. Unexpectedly, minor co-amplifications of NUP98 and 11q22.1 loci were also observed in other HeLa sublines, but on rearranged chromosomes 11. Altogether, this study reveals that distinct genomic rearrangements affecting NUP98 are associated with the formation of GLFG bodies in specific HeLa sublines.
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- 2016
26. NUP98 is rearranged in 3.8% of pediatric AML forming a clinical and molecular homogenous group with a poor prognosis
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Isabelle Radford-Weiss, Arnaud Petit, Audrey Bidet, Dominique Penther, Wendy Cuccuini, M Pasquet, Guy Leverger, Marie-Pierre Pages, Eric Delabesse, Christine Lefebvre, Collonge-Rame Ma, Bart-Delabesse E, Stéphanie Struski, Marina Lafage-Pochitaloff, Isabelle Luquet, Cyril Broccardo, Puiseux C, Nathalie Nadal, Baptiste Gaillard, Naïs Prade, Pierre Bories, Carine Gervais, Carole Barin, Catherine Roche-Lestienne, Francine Mugneret, and Stéphanie Lagarde
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0301 basic medicine ,Male ,Cancer Research ,Myeloid ,Oncogene Proteins, Fusion ,Biology ,Translocation, Genetic ,Epigenesis, Genetic ,Fusion gene ,03 medical and health sciences ,0302 clinical medicine ,Gene Frequency ,hemic and lymphatic diseases ,CEBPA ,medicine ,Biomarkers, Tumor ,Humans ,Exome ,Child ,WT1 Proteins ,Exome sequencing ,Alleles ,In Situ Hybridization, Fluorescence ,NUP98 Gene ,Gene Expression Regulation, Leukemic ,breakpoint cluster region ,Infant, Newborn ,High-Throughput Nucleotide Sequencing ,Infant ,Hematology ,medicine.disease ,Prognosis ,Nuclear Pore Complex Proteins ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,fms-Like Tyrosine Kinase 3 ,030220 oncology & carcinogenesis ,Child, Preschool ,Mutation ,Cancer research ,CCAAT-Enhancer-Binding Proteins ,Female ,Signal Transduction - Abstract
Pediatric acute myeloid leukemia (AML) is a rare disease whose prognosis is highly variable according to factors such as chromosomal abnormalities. Recurrent genomic rearrangements are detected in half of pediatric AML by karyotype. NUcleoPorin 98 (NUP98) gene is rearranged with 31 different fusion partner genes. These rearrangements are frequently undetected by conventional cytogenetics, as the NUP98 gene is located at the end of the chromosome 11 short arm (11p15). By screening a series of 574 pediatric AML, we detected a NUP98 rearrangement in 22 cases (3.8%), a frequency similar to CBFB-MYH11 fusion gene (4.0%). The most frequent NUP98 fusion gene partner is NSD1. These cases are homogeneous regarding their biological and clinical characteristics, and associated with bad prognosis only improved by bone marrow transplantation. We detailed the biological characteristics of these AML by exome sequencing which demonstrated few recurrent mutations (FLT3 ITD, WT1, CEBPA, NBPF14, BCR and ODF1). The analysis of the clonal structure in these cases suggests that the mutation order in the NUP98-rearranged pediatric AML begins with the NUP98 rearrangement leading to epigenetic dysregulations then followed by mutations of critical hematopoietic transcription factors and finally, activation of the FLT3 signaling pathway.
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- 2016
27. 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
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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 )
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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.
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- 2016
28. An Early Thymic Precursor Phenotype Predicts Outcome Exclusively in HOXA-Overexpressing Adult T-ALL: A GRAALL Study
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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]
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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.
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- 2015
29. Chronic lymphocytic leukemia and prolymphocytic leukemia with MYC translocations: a subgroup with an aggressive disease course
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Peter Vandenberghe, Anne Hagemeijer, Natalie Put, Virginie Eclache, Peter Konings, Lucienne Michaux, Elise Chapiro, Sophy Laibe, Carine Gervais, Christine Lefebvre, Hélène Poirel, Stéphanie Struski, Florence Nguyen-Khac, Yves Moreau, Nicole Dastugue, Iwona Wlodarska, Katrina Rack, M J Mozziconacci, Nathalie Gachard, Sandra Fert-Ferrer, Carole Barin, Katrien Van Roosbroeck, Caroline Brusselmans, Peter Meeus, Benoit Quilichini, and Isabelle Radford-Weiss
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Male ,Monosomy ,medicine.medical_specialty ,Pathology ,Chromosomes, Human, Pair 22 ,Chronic lymphocytic leukemia ,Genes, myc ,Chromosomal translocation ,Biology ,Translocation, Genetic ,Cohort Studies ,Leukemia, Prolymphocytic ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Neoplasm Invasiveness ,Prolymphocytic leukemia ,Aged ,Retrospective Studies ,Aged, 80 and over ,Chromosomes, Human, Pair 14 ,Hematology ,medicine.diagnostic_test ,General Medicine ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Leukemia ,Case-Control Studies ,Chromosomes, Human, Pair 2 ,Disease Progression ,Cancer research ,Female ,CD5 ,Chromosomes, Human, Pair 8 ,Fluorescence in situ hybridization - Abstract
Translocations involving MYC are rare in chronic lymphocytic leukemia (CLL), and up to now, their prognostic significance remains unclear. We report the characteristics of 21 patients with CLL and nine patients with prolymphocytic leukemia (PLL), diagnosed in multiple centers (n = 13), which showed an MYC translocation demonstrated by fluorescence in situ hybridization. The prevalence was estimated to be
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- 2011
30. Onset of autoimmune lymphoproliferative syndrome (ALPS) in humans as a consequence of genetic defect accumulation
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Cécile Daussy, Gérard Michel, Aude Magerus-Chatinet, Filomeen Haerynck, Sophie Cluet-Dennetiere, Capucine Picard, Serge Romana, Alain Fischer, Nina Lanzarotti, Frédéric Rieux-Laucat, Christine Bole-Feysot, Catherine Schaffner, Mohammed Zarhrate, Isabelle Radford-Weiss, Marie-Claude Stolzenberg, Bénédicte Neven, and Peter D. Arkwright
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EXPRESSION ,Adult ,Male ,Heterozygote ,Adolescent ,FEATURES ,LYMPHOCYTE APOPTOSIS ,Loss of Heterozygosity ,Lymphocytes, Null ,Penetrance ,Biology ,medicine.disease_cause ,FAMILIES ,DISEASE ,Loss of heterozygosity ,Young Adult ,Germline mutation ,Medicine and Health Sciences ,medicine ,Humans ,fas Receptor ,Allele ,Germ-Line Mutation ,SOMATIC FAS MUTATIONS ,Autoimmune disease ,Mutation ,Models, Genetic ,Chromosomes, Human, Pair 10 ,Autoimmune Lymphoproliferative Syndrome ,Genetic Variation ,General Medicine ,Middle Aged ,Uniparental Disomy ,INTERLEUKIN-10 ,medicine.disease ,Uniparental disomy ,Pedigree ,Protein Structure, Tertiary ,Autoimmune lymphoproliferative syndrome ,Immunology ,T-CELLS ,Commentary ,Female ,CD8 ,Research Article ,Signal Transduction - Abstract
Autoimmune diseases develop in approximately 5% of humans. They can arise when self-tolerance checkpoints of the immune system are bypassed as a consequence of inherited mutations of key genes involved in lymphocyte activation, survival, or death. For example, autoimmune lymphoproliferative syndrome (ALPS) results from defects in self-tolerance checkpoints as a consequence of mutations in the death receptor-encoding gene TNF receptor superfamily, member 6 (TNFRSF6; also known as FAS). However, some mutation carriers remain asymptomatic throughout life. We have now demonstrated in 7 ALPS patients that the disease develops as a consequence of an inherited TNFRSF6 heterozygous mutation combined with a somatic genetic event in the second TNFRSF6 allele. Analysis of the patients' CD4(-)CD8(-) (double negative) T cells--accumulation of which is a hallmark of ALPS--revealed that in these cells, 3 patients had somatic mutations in their second TNFRSF6 allele, while 4 patients had loss of heterozygosity by telomeric uniparental disomy of chromosome 10. This observation provides the molecular bases of a nonmalignant autoimmune disease development in humans and may shed light on the mechanism underlying the occurrence of other autoimmune diseases.
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- 2011
31. Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia
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Marc Benhamou, Jean-Antoine Ribeil, Séverine Coulon, Hervé Dombret, Philippe Dessen, Saurabh Agarwal, Carole Beaumont, Renato C. Monteiro, Jérôme Naudin, Marie-Thérèse Rubio, Nicolas Boissel, Houda Tamouza, Danielle Canioni, Pamella Huey Mei Wang, Olivia Chandesris, Céline Callens, Elizabeth Macintyre, Olivier Hermine, Ivan C. Moura, Etienne Paubelle, Emmanuel Raffoux, Vahid Asnafi, and Isabelle Radford-Weiss
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Acute promyelocytic leukemia ,Myeloid ,Cellular differentiation ,Immunology ,Mutation, Missense ,Retinoic acid ,Biology ,Iron Chelating Agents ,Models, Biological ,Calcitriol receptor ,Article ,Glutarates ,chemistry.chemical_compound ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Immunology and Allergy ,Arsenic trioxide ,Cholecalciferol ,Leukemia ,JNK Mitogen-Activated Protein Kinases ,Myeloid leukemia ,Hematopoietic Stem Cells ,Hypoxia-Inducible Factor 1, alpha Subunit ,medicine.disease ,Isocitrate Dehydrogenase ,Hematopoiesis ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,chemistry ,Neoplastic Stem Cells ,Cancer research ,Reactive Oxygen Species ,NADP - Abstract
Differentiating agents have been proposed to overcome the impaired cellular differentiation in acute myeloid leukemia (AML). However, only the combinations of all-trans retinoic acid or arsenic trioxide with chemotherapy have been successful, and only in treating acute promyelocytic leukemia (also called AML3). We show that iron homeostasis is an effective target in the treatment of AML. Iron chelating therapy induces the differentiation of leukemia blasts and normal bone marrow precursors into monocytes/macrophages in a manner involving modulation of reactive oxygen species expression and the activation of mitogen-activated protein kinases (MAPKs). 30% of the genes most strongly induced by iron deprivation are also targeted by vitamin D3 (VD), a well known differentiating agent. Iron chelating agents induce expression and phosphorylation of the VD receptor (VDR), and iron deprivation and VD act synergistically. VD magnifies activation of MAPK JNK and the induction of VDR target genes. When used to treat one AML patient refractory to chemotherapy, the combination of iron-chelating agents and VD resulted in reversal of pancytopenia and in blast differentiation. We propose that iron availability modulates myeloid cell commitment and that targeting this cellular differentiation pathway together with conventional differentiating agents provides new therapeutic modalities for AML.
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- 2010
32. Gain of the short arm of chromosome 2 (2p) is a frequent recurring chromosome aberration in untreated chronic lymphocytic leukemia (CLL) at advanced stages
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Lauren Veronese, Marc De Braekeleer, Christine Terré, Isabelle Radford-Weiss, Sylvie Taviaux, Nathalie Leporrier, Hélène Merle-Béral, Dominique Leroux, Hossein Mossafa, Florence Nguyen-Khac, Elise Chapiro, Sandra Fert-Ferrer, Evelyne Callet-Bauchu, Frederic Davi, Olivier Bernard, Laurent Sutton, Françoise Brizard, Claude Lesty, Stéphanie Struski, Christian Bastard, Isabelle Tigaud, and Sophie Raynaud
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Chromosome Aberrations ,Cancer Research ,Poor prognosis ,Mrna expression ,Advanced stage ,Gene Dosage ,Chromosome ,Hematology ,Biology ,Leukemia, Lymphocytic, Chronic, B-Cell ,Chromosome aberration ,Molecular biology ,Oncology ,Chromosomes, Human, Pair 2 ,Cancer research ,Humans ,Abnormality ,IGHV@ ,neoplasms ,Untreated Chronic Lymphocytic Leukemia - Abstract
Using array-based CGH, we identified 2p gain in 22/78 (28%) untreated Binet stages B/C CLL, which was the second most frequent copy number change after 13q deletion. It never occurred as a sole abnormality and was associated with other changes (6q deletion; 1p gain). The region of 2p gain frequently included two oncogenes, REL and MYCN. All patients with gain of REL were unmutated for IGHV (p=0.03). Gain of MYCN was associated with increased mRNA expression (p=0.005), suggesting a pathogenic role for MYCN. Gain of 2p appears to be a marker of progression and may contribute to the poor prognosis.
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- 2010
33. Presentation and Long-Term Follow-up of Refractory Celiac Disease: Comparison of Type I With Type II
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Georgia Malamut, Olivier Hermine, Diane Damotte, Bertrand Meresse, Christophe Cellier, Virginie Verkarre, Aurelien Amiot, Thierry Lecomte, Elizabeth Macintyre, Nicole Brousse, Jacques Cosnes, Isabelle Radford-Weiss, Anne Lavergne-Slove, Yoram Bouhnik, Jean-Frederic Colombel, Pauline Afchain, Ludovic Trinquart, Nadine Cerf-Bensussan, Matthieu Allez, and Jean-Charles Delchier
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Multivariate analysis ,CD3 Complex ,CD8 Antigens ,Disease ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Adrenal Cortex Hormones ,Internal medicine ,Humans ,Medicine ,Survival rate ,2. Zero hunger ,Hepatology ,business.industry ,Middle Aged ,medicine.disease ,Immunohistochemistry ,3. Good health ,Lymphoma ,Survival Rate ,Celiac Disease ,030220 oncology & carcinogenesis ,Intraepithelial lymphocyte ,Enteropathy-associated T-cell lymphoma ,Female ,030211 gastroenterology & hepatology ,business ,Follow-Up Studies - Abstract
Refractory celiac disease (RCD) was recently subdivided into 2 subtypes (RCD I and II) based on a normal or abnormal phenotype of intraepithelial lymphocytes (IELs), respectively. It is not clear, however, if these 2 entities differ in their presentation at diagnosis or long-term outcome. We compared the clinical and biological characteristics of RCD I and RCD II at diagnosis, the risk of developing an overt lymphoma, and the predictive factors of survival.Medical files of 14 patients with RCD I and 43 with RCD II were analyzed retrospectively. Predictive factors of overt lymphoma and survival were studied in univariate and multivariate analyses.At diagnosis, malnutrition, ulcerative jejunitis, and lymphocytic gastritis were more common in patients with RCD II than RCD I (P.05). Overt lymphomas occurred in 2 patients with RCD I and 16 with RCD II. In the univariate analysis, abnormal IEL phenotype and increased age at diagnosis of RCD were predictive factors for overt lymphoma. Abnormal IEL phenotype (P.01), clonality (P= .01), and overt lymphoma (P= .001) predicted short survival time. Only abnormal IEL phenotype (P= .03) and overt lymphoma (P= .04) were predictive in the multivariate analysis. The 5-year survival rate was 93% in patients with RCD I and 44% with RCD II.RCD II has a much more severe presentation and prognosis than patients with RCD I;44% of patients with RCD II survive 5 years after diagnosis. Abnormal IEL phenotype is a predictive factor but not a necessary condition for the development of overt lymphoma.
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- 2009
34. The most frequent t(14;19)(q32;q13)-positive B-cell malignancy corresponds to an aggressive subgroup of atypical chronic lymphocytic leukemia
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Isabelle Radford-Weiss, Olivier Bernard, Carole Barin, Sophie Raynaud, M J Mozziconacci, Roland Berger, Sylvie Ramond, Florence Nguyen-Khac, Dominique Leroux, Francine Mugneret, H. Merle-Beral, Joris Andrieux, Eric Lippert, Pascaline Talmant, Stéphanie Struski, Françoise Berger, Christine Lefebvre, Christian Bastard, Frederic Davi, Christine Terré, Martine Jotterand, Pascale Felman, Hossein Mossafa, Evelyne Callet-Bauchu, Isabelle Luquet, and Elise Chapiro
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Adult ,Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Chronic lymphocytic leukemia ,Biology ,Malignancy ,Translocation, Genetic ,Immunophenotyping ,B-Cell Lymphoma 3 Protein ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,Leukemia, B-Cell ,medicine ,Humans ,B cell malignancy ,Aged ,Aged, 80 and over ,Chromosomes, Human, Pair 14 ,NF-kappa B ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Oncology ,Female ,Chromosomes, Human, Pair 19 ,Transcription Factors - Abstract
The most frequent t(14;19)(q32;q13)-positive B-cell malignancy corresponds to an aggressive subgroup of atypical chronic lymphocytic leukemia
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- 2008
35. HOX11L2/TLX3 is transcriptionally activated through T-cell regulatory elements downstream of BCL11B as a result of the t(5;14)(q35;q32)
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Virginie Penard-Lacronique, Isabelle André-Schmutz, Xin-Ying Su, Roland Berger, Paola Ballerini, Claudie Lemercier, Véronique Della-Valle, Francine Mugneret, Serge Romana, Michel Lessard, Isabelle Radford-Weiss, Marina Lafage-Pochitaloff, Olivier Bernard, Génétique des hémopathies humaines ( EMI 210 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Developpement Normal et Pathologique du Système Immunitaire, Contrôle moléculaire de la réponse immune specifique, Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Cytogénétique, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Service d'Hématologie Biologique, Assistance publique - Hôpitaux de Paris (AP-HP), Laboratoire d'Hématologie, CHU Strasbourg, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Génétique des hémopathies humaines (EMI 210), 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 Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [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), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
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Oncogene Proteins, Fusion ,Transcription, Genetic ,T-Lymphocytes ,BCL11B ,Chromosomal translocation ,MESH : Promoter Regions, Genetic ,MESH : Oncogene Proteins, Fusion ,Biochemistry ,Jurkat cells ,Translocation, Genetic ,Jurkat Cells ,MESH : Chromosomes, Human, Pair 5 ,0302 clinical medicine ,MESH : Translocation, Genetic ,Transcription (biology) ,MESH: Jurkat Cells ,Leukemia-Lymphoma, Adult T-Cell ,MESH: Leukemia-Lymphoma, Adult T-Cell ,MESH : Homeodomain Proteins ,Promoter Regions, Genetic ,MESH : Jurkat Cells ,Oncogene Proteins ,0303 health sciences ,MESH : Chromosomes, Human, Pair 14 ,MESH : Oncogene Proteins ,MESH : Tumor Suppressor Proteins ,Cell Differentiation ,Hematology ,Transfection ,MESH: Translocation, Genetic ,DNA-Binding Proteins ,medicine.anatomical_structure ,MESH: Repressor Proteins ,030220 oncology & carcinogenesis ,Chromosomes, Human, Pair 5 ,MESH : DNA-Binding Proteins ,MESH : Repressor Proteins ,MESH : Cell Differentiation ,MESH: Cell Differentiation ,MESH: Chromosomes, Human, Pair 5 ,T cell ,Immunology ,Biology ,03 medical and health sciences ,MESH: Oncogene Proteins ,MESH: Promoter Regions, Genetic ,MESH: Homeodomain Proteins ,medicine ,Humans ,MESH: Tumor Suppressor Proteins ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,030304 developmental biology ,Chromosomes, Human, Pair 14 ,Homeodomain Proteins ,MESH : T-Lymphocytes ,MESH: Humans ,Recombinase activity ,Tumor Suppressor Proteins ,MESH: Transcription, Genetic ,MESH : Humans ,MESH : Transcription, Genetic ,Cell Biology ,T lymphocyte ,Molecular biology ,MESH : Leukemia-Lymphoma, Adult T-Cell ,Repressor Proteins ,MESH: T-Lymphocytes ,MESH: Chromosomes, Human, Pair 14 ,MESH: DNA-Binding Proteins ,MESH: Oncogene Proteins, Fusion - Abstract
International audience; The t(5;14)(q35;q32) chromosomal translocation is specifically observed in up to 20% of childhood T-cell acute lymphoblastic leukemia (T-ALL). It affects the BCL11B/CTIP2 locus on chromosome 14 and the RANBP17-TLX3/HOX11L2 region on chromosome 5. It leads to ectopic activation of TLX3/HOX11L2. To investigate the reasons of the association between t(5;14) and T-ALL, we isolated the translocation breakpoints in 8 t(5;14) patients. Sequence analyses did not involve recombinase activity in the genesis of the translocation. We used DNAse1 hypersensitive experiments to locate transcriptional regulatory elements downstream of BCL11B. By transient transfection experiments, 2 of the 6 regions demonstrated cis-activation properties in T cells and were also effective on the TLX3 promoter. Our data indicate that the basis of the specific association between t(5;14) and T-ALL lies on the juxtaposition of TLX3 to long-range cis-activating regions active during T-cell differentiation.
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- 2006
36. Overexpression of CEBPA resulting from the translocation t(14;19)(q32;q13) of human precursor B acute lymphoblastic leukemia
- Author
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Florence Nguyen-Khac, Stéphanie Struski, Roland Berger, Olivier Bernard, Carole Barin, Sandra Fert-Ferrer, Jonathan C. Strefford, Isabelle Radford-Weiss, Michel Lessard, Odile Maarek, Christine J. Harrison, Christian Bastard, Elise Chapiro, Lisa J. Russell, Véronique Della-Valle, and Hélène Cavé
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Adult ,Male ,Immunoglobulin gene ,Myeloid ,Immunology ,Biology ,medicine.disease_cause ,Biochemistry ,Translocation, Genetic ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,hemic and lymphatic diseases ,Acute lymphocytic leukemia ,CEBPA ,medicine ,Humans ,RNA, Neoplasm ,Child ,Aged ,Chromosomes, Human, Pair 14 ,Gene Rearrangement ,Genes, Immunoglobulin ,Myeloid leukemia ,Cell Biology ,Hematology ,Gene rearrangement ,Middle Aged ,medicine.disease ,Molecular biology ,Gene Expression Regulation, Neoplastic ,Haematopoiesis ,medicine.anatomical_structure ,CCAAT-Enhancer-Binding Proteins ,Cancer research ,Female ,Immunoglobulin Heavy Chains ,Carcinogenesis ,Chromosomes, Human, Pair 19 - Abstract
Subtle variation in the expression or function of a small group of transcription factors can drive leukemogenesis. The CEBPA protein is known to regulate the balance between cell proliferation and differentiation during early hematopoietic development and myeloid differentiation. In human myeloid leukemia, CEBPA is frequently inactivated by mutation and indirect and posttranslational mechanisms, in keeping with tumor suppressor properties. We report that CEBPA is activated by juxtaposition to the immunoglobulin gene enhancer upon its rearrangement with the immunoglobulin heavy-chain locus in precursor B-cell acute lymphoblastic leukemia harboring t(14;19)(q32;q13). Overexpression of apparently normal CEBPA RNA or protein was observed in 6 patients. These data indicate that CEBPA may exhibit oncogenic as well as tumor suppressor properties in human leukemogenesis.
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- 2006
37. Deciphering leukemic B-cell chronic lymphoproliferative disorders
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Isabelle Radford-Weiss, Chantal Brouzes, Rémi Letestu, M. Guesnu, Florence Ajchenbaum-Cymbalista, Vincent Levy, Valérie Ugo, Françoise Valensi, Nathalie Leporrier, Sylvie Ramond, Jean-Yves Perrot, Joelle Nataf, Françoise Picard, Véronique Salaun, and Xavier Troussard
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,Lymphoma, B-Cell ,Chronic lymphocytic leukemia ,Lymphoproliferative disorders ,CD5 Antigens ,Immunophenotyping ,Cohort Studies ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Cyclin D1 ,Prospective Studies ,B cell ,Aged ,CD20 ,Hematology ,biology ,business.industry ,Cell Cycle ,Middle Aged ,Antigens, CD20 ,Prognosis ,medicine.disease ,Lymphoproliferative Disorders ,Lymphoma ,medicine.anatomical_structure ,biology.protein ,Female ,CD5 ,business ,Cyclin-Dependent Kinase Inhibitor p27 - Abstract
Diagnosis of leukemic B-cell chronic lymphoproliferative disorders (B-CLPD) is a frequent challenge in hematology. In this multicentric study, we prospectively studied 165 new consecutive leukemic patients with B-CLPD selected on the basis of Royal Marsden Hospital scoring system < or =3. The primary aim of the study was to try to decipher the atypical cases and identify homogenous subgroups. Overall, morphological examination contributed to diagnosis in only 20% cases, all of them CD5 negative. Thirty additional cases were CD5 negative suggestive of leukemic marginal zone lymphoma in most cases. The significantly poorer survival of the 26 cyclin D1 positive cases justifies recommending its systematic determination among atypical B-CLPD. CD20 expression segregated clearly two subgroups among CD5 positive cyclin D1 negative B-CLPD. The 17 patients with the CD20 dim profile represent a homogeneous subgroup very close to typical B-cell chronic lymphocytic leukemia (B-CLL) on morphological, phenotypical and cytogenetical criteria. In contrast, the subgroup of 51 patients with a CD20 bright profile is heterogeneous. Their significantly lower p27 expression level suggest the presence of a proliferative component, underlying a more aggressive disease. Further genomic studies are warranted to establish their precise nature. These cases should not be included in the same therapeutic trials as B-CLL.
- Published
- 2006
38. Transient familial haemophagocytic lymphohistiocytosis reactivation post-CD34 haematopoietic stem cell transplantation
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Marina Cavazzana-Calvo, Capucine Picard, Stéphane Blanche, F Le Deist, Isabelle Radford-Weiss, Alain Fischer, Sophie Caillat-Zucman, G de Saint Basile, H Almousa, and Marie Ouachée-Chardin
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Male ,Pathology ,medicine.medical_specialty ,Histiocytosis, Non-Langerhans-Cell ,T-Lymphocytes ,medicine.medical_treatment ,T cell ,Antigens, CD34 ,Hematopoietic stem cell transplantation ,Biology ,Recurrence ,Lymphocyte homeostasis ,medicine ,Humans ,Transplantation, Homologous ,Postoperative Period ,Cell Proliferation ,Retrospective Studies ,Transplantation Chimera ,Hemophagocytic lymphohistiocytosis ,Hematopoietic Stem Cell Transplantation ,Infant ,Hematology ,medicine.disease ,Transplantation ,Haematopoiesis ,surgical procedures, operative ,medicine.anatomical_structure ,Immunology ,Bone marrow ,Stem cell - Abstract
Familial haemophagocytic lymphohistiocytosis (FHLH) is a genetic disorder caused by defective lymphocyte cytotoxicity, resulting in impaired lymphocyte homeostasis and macrophage infiltration of solid tissues and bone marrow, with extensive haemophagocytosis. It is invariably fatal unless treated by allogeneic haematopoietic stem cell transplantation (HSCT). In a retrospective analysis of 11 cases of FHLH, transplanted in one centre between January 1999 and December 2003, it was found that host T cell expansion occurred early after HSCT in a setting of a viral infection (cytomegalovirus and Epstein-Barr virus respectively) in two cases who received T cell-depleted HSCT. Transient recurrence of clinical and biological manifestations of FHLH was observed, despite evidence for donor cell engraftment. Secondary development of donor T cells led to stable mixed chimaerism and sustained remission of FHLH. Detection of host-derived T cells soon after HSCT in a patient with FHLH should thus not mistakenly be taken as a manifestation of graft rejection.
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- 2005
39. Human herpesvirus 8 (HHV-8)-associated peritoneal primary effusion lymphoma (PEL) in two HIV-negative elderly patients
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Jean-Paul Fermand, Emmanuelle Boulanger, Isabelle Radford-Weiss, Olivier Hermine, Antoine Gessain, Véronique Meignin, and Nicole Brousse
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Male ,Pathology ,medicine.medical_specialty ,Lymphoma, B-Cell ,CD30 ,viruses ,Fatal Outcome ,Immunophenotyping ,immune system diseases ,HIV Seronegativity ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Gammaherpesvirinae ,Aged ,Aged, 80 and over ,biology ,business.industry ,Castleman disease ,virus diseases ,Herpesviridae Infections ,Hematology ,medicine.disease ,biology.organism_classification ,Lymphoma ,Serous fluid ,Effusion ,DNA, Viral ,Herpesvirus 8, Human ,Female ,Primary effusion lymphoma ,business - Abstract
Human herpesvirus 8 (KSHV/HHV-8) is associated with all forms of Kaposi sarcoma (KS), with a rare high-grade B-cell non-Hodgkin lymphoma characterized by serous effusions in body cavities called primary effusion lymphoma (PEL) and with some forms of multicentric Castleman disease (MCD). Although mostly observed during AIDS, such disorders have also been described with a lower incidence in human immunodeficiency virus-negative patients. We describe here the features of two novel cases of AIDS-unrelated PEL. Two patients, a 78-year-old man (case 1) and a 86-year-old woman (case 2), both of French origin, presented exudative ascitic effusion containing numerous KSHV/HHV-8(+) EBV(-) large lymphomatous cells of B-cell clonal origin, characterized by a CD45(+) CD30(+) CD19(-) CD20(-) immunophenotype. The PEL tumor cells harbored a homogenous and isolated trisomy 12 in case 1 and an aberrant expression of the T-cell lineage antigen CD7 in case 2. Both patients were lymphopenic at the time of PEL diagnosis and rapidly died with progressive lymphoma. Moreover, patient 2 had a previous history of classic KS and MCD clinically improved after treatment with all-trans-retinoid acid and a concomitant metastatic breast adenocarcinoma. Compared to AIDS-related PEL, these two cases displayed distinct features in particular the advanced age of patients, as observed for Mediterranean KS, and the absence of EBV coinfection.
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- 2004
40. CALM-AF10 is a common fusion transcript in T-ALL and is specific to the TCR lineage
- Author
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D Leboeuf, Elizabeth Macintyre, Agnès Buzyn, Nicole Dastugue, Richard Garand, Eric Delabesse, Marina Lafage-Pochitaloff, C. Charrin, Isabelle Radford-Weiss, Vahid Asnafi, C Bayle, and Xavier Troussard
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medicine.medical_specialty ,Lineage (genetic) ,Myeloid ,medicine.diagnostic_test ,Immunology ,Cytogenetics ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Molecular biology ,medicine.anatomical_structure ,Immunophenotyping ,Fusion transcript ,Acute lymphocytic leukemia ,medicine ,CD5 ,Fluorescence in situ hybridization - Abstract
The t(10;11)(p13-14;q14-21) associated with CALM-AF10 is considered to be rare and associated with a variety of acute lymphoid and myeloid leukemias. Twelve (9%) of 131 unselected T-cell acute lymphoid leukemias (T-ALLs) expressed CALM-AF10 by reverse transcription-polymerase chain reaction or fluorescence in situ hybridization (or both), including 8% of children and 10% of adults, of whom only half demonstrated a t(10;11) by classical cytogenetics. CALM-AF10 was not found in T-cell-receptor alphabeta (TCRalphabeta) lineage T-ALLs, as defined by expression of TCRalphabeta, cytoplasmic TCRbeta, or TCRbetaVDJ rearrangement in immature cytoplasmic TCRbeta- cases, compared with 19% of TCRgammadelta T-ALLs and 33% of immature delta/gamma T-ALLs. The latter differed from their CALM-AF10- immature counterparts by a CD5+/CD2-phenotype, as found in TCRgammadelta but not TCRalphabeta T-ALLs and in their TCRgamma and TCRdelta configurations, altogether suggesting that CALM-AF10+ immature delta/gammaT-ALLs are TCRgammadelta precursors and that, within T-ALL, CALM-AF10 is specific for this lineage. Nine of 12 immature CALM-AF10 T-ALLs demonstrated 3' fusion transcripts, whereas 6 of 7 TCRgammadelta T-ALLs demonstrated 5' fusion transcripts. The latter retain the AF10 extended LAP/PHD domain necessary for homo-oligomerization. All 8 patients with CALM-AF10+TCRgammadelta T-ALLs are alive, compared with only 3 of 12 with immature CALM-AF10+ T-ALLs. Six CALM-AF10+ non-T acute leukemias all expressed CD7 and demonstrated T-restricted TCRdelta rearrangements, suggesting that they may also be related to the TCRgammadelta lineage. CALM-AF10 is therefore the most common fusion protein in T-ALL. It requires molecular and immunophenotypic characterization for appropriate prognostic evaluation and should be included in diagnostic screening panels of T-ALL and immature acute leukemias. Analysis of immature CALM-AF10+ leukemias will also facilitate analysis of the early stages of development of the TCRgammadelta lineage.
- Published
- 2003
41. Typical essential thrombocythaemia does not express bcr-abelson fusion transcript
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Eric Delabesse, Ghandi Damaj, Vahid Asnafi, M. Rachid, François Lefrère, Olivier Hermine, C. Le Bihan, Isabelle Radford-Weiss, E Macintyre, and Bruno Varet
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Oncology ,medicine.medical_specialty ,Pathology ,breakpoint cluster region ,Cytogenetics ,Hematology ,Biology ,Philadelphia chromosome ,medicine.disease ,Reverse transcription polymerase chain reaction ,Basophilia ,Fusion transcript ,Elevated platelet count ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Prospective cohort study ,neoplasms - Abstract
Essential thrombocythaemia (ET) is a chronic myeloproliferative disorder (MPD) characterized by an elevated platelet count and no identifiable underlying primary cause. According to the diagnostic criteria of the Polycythemia Vera Study Group (PVSG), ET lacks features diagnostic for other MPDs, including the Philadelphia chromosome (Ph) or bcr-abl rearrangement. Recently, some authors have reported bcr-abl transcript positivity in ET patients, but these findings remain controversial. The aim of this study was to investigate whether the bcr-abl transcript could be found in ET patients and to verify the hypothesis of a new ET variant. ET patients (n = 121) with a median age at diagnosis of 55 years were enrolled. The bcr-abl transcript status was examined by multiplex reverse transcription-polymerase chain reaction. Only two cases were positive for bcr-abl, one of which had the Ph at diagnosis. The positive bcr-abl transcript was associated, in both cases, with mild basophilia at diagnosis. After a median follow-up of 43 months (0-309 months), two patients in the bcr-abl-negative group developed Ph and bcr-abl-negative acute myeloid leukaemia (AML). In contrast, one of the two patients in the bcr-abl-positive group died from AML 13 years after diagnosis. In conclusion, our data on a large group of patients shows the rarity of the bcr-abl transcript in well-established ET. However, a subset of patients with apparent ET and basophilia may express the transcript and may constitute a novel entity intermediate between chronic myeloid leukaemia (CML) and typical ET. A prospective study is warranted in order to define better the clinical and biological characteristics of bcr-abl-expressing ET.
- Published
- 2002
42. Clonal B-Cell Lymphocytosis with Marginal Zone Features and Splenic Marginal Zone Lymphoma Share a Similar Cytogenetic and Mutational Profile
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Hélène Guermouche, David Sibon, Olivier Kosmider, Bénédicte Deau, Coralie Derrieux, Barbara Burroni, Didier Bouscary, Olivier Hermine, Richard Delarue, Julie Bruneau, Isabelle Radford-Weiss, Paul Legendre, and Nicolas Chapuis
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medicine.medical_specialty ,Univariate analysis ,Monosomy ,Lymphocytosis ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Immunophenotyping ,B symptoms ,Internal medicine ,medicine ,Monoclonal B-cell lymphocytosis ,Splenic marginal zone lymphoma ,medicine.symptom ,business ,Diffuse large B-cell lymphoma - Abstract
Introduction: Clonal B-cell lymphocytosis with marginal zone features (CBL-MZ) is a non-CLL type B-cell monoclonal lymphocytosis that has been recently recognized in the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms. Whether CBL-MZ corresponds to the early stage of splenic marginal zone lymphoma (SMZL) is not clearly defined. The aim of the study was to compare CBL-MZ and SMZL in patients diagnosed during the same period in two French university hospitals. Methods: We performed a retrospective study including all consecutive patients with a diagnosis of CBL-MZ or SMZL between 2010 and 2014. For the purpose of the present study, all CBL-MZ and SMZL were reclassified according to the 2016 WHO classification. Patient and disease characteristics comprised clinical data, immunophenotyping of lymphocytes by flow cytometry, cytogenetic studies (G-banding and TP53 FISH) and targeted gene sequencing (TP53, NOTCH2 and MYD88). We assessed progression-free survival (PFS), lymphoma-specific survival (LSS), overall survival (OS) and cumulative incidence of histologic transformation. Results: Forty-one patients were diagnosed with CBL-MZ (n=15) or SMZL (n=26) on consensus review. None had HCV infection. Median age was 74 years (range 43-93). At diagnosis, B symptoms (7% vs 46%, p=0.009), elevated lactate dehydrogenase (13% vs 50%, p=0.023) and elevated β2-microglobulin (50% vs 93%, p=0.039) were significantly more frequent in SMZL patients. HPLL score A was more frequent in patient with CBL-MZ (93% vs 58%, p=0.003). On lymphocyte immunophenotyping, CD23 was expressed only in SMZL (0% vs 38%, p=0.015). Aberrant karyotype was displayed in 5/7 CBL-MZ and 15/18 of SMZL (p=0.591). Fourteen patients (56%; 2 CBL-MZ and 12 SMZL, p=0.177) had at least 3 chromosomal abnormalities and were considered to have a complex karyotype. There was no significant difference between CBL-MZ and SMZL for the frequency of detection of +3, +12, +18, del(7q) or 14q alterations. A chromosome 17p abnormality or monosomy 17 was seen in 12/25 patients (48%) without significant difference between CBL-MZ and SMZL, and was confirmed in 11/11 cases by TP53 FISH analysis (one patient had an isochromosome 17q and TP53 FISH was not done). In 11 other patients, no TP53 deletion was detected by FISH. In the 2 remaining patients (one normal karyotype and one abnormal karyotype without abnormal 17p) there was no more material for FISH analysis. TP53 mutation was present in 1/15 (7%) CBL-MZ and 6/22 (27%) SMZL (p=0.161), NOTCH2 mutation in 1/15 (7%) CBL-MZ and 3/22 (14%) SMZL (p=0,632) and MYD88 mutation in 1/15 (7%) CBL-MZ and 3/22 (14%) SMZL (p=0.632). After a median follow-up of 47 months (CBL-MZ, 52 months; SMZL, 46 months, p=0.771), no CBL-MZ patients had event (progression, histologic transformation or death) or started treatment, whereas 24/26 (92%) SMZL patients started a first-line treatment (chemotherapy in 62%, rituximab in 42% and/or splenectomy in 39%). Twelve SMZL patients (50% of treated patients) relapsed or progressed after the first-line treatment. Among them, 6 had histologic transformation, either in diffuse large B-cell lymphoma (DLBCL, n=5) or Hodgkin lymphoma (HL, n=1). Finally, 5 SMZL patients died (3 of DLBCL, 1 of HL, 1 of SMZL). Overall, 4-year PFS was 100% and 31% (95% CI, 13% to 49%) for CBL-MZ and SMZL, respectively (p=0.002); 4-year LSS was 100% and 77% (95% CI, 61% to 93%) for CBL-MZ and SMZL, respectively (p=0.26); and 4-year OS was 100% and 71% (95% CI, 54% to 88%) for CBL-MZ and SMZL, respectively (p=0.25). Clinical, laboratory, cytogenetic and molecular features were subjected to univariate analyses to evaluate their impact on PFS, LSS, OS and histologic transformation in SMZL patients. In univariate analysis for PFS, only NOTCH2 mutations and TP53 inactivation (i.e. del(17p) or TP53 mutations) predicted poorer PFS, but in multivariate analysis NOTCH2 mutations were the sole factor significantly affecting PFS rates (p=0.041). For LSS, OS and histologic transformation, no prognostic factor was identified in univariate analysis. Conclusions: Our data suggest that CBL-MZ and SMZL share a similar cytogenetic and mutational profile. These findings suggest the possible involvement of a common oncogenic mechanism in the development of these lymphoid neoplasms. Disclosures Hermine: Novartis: Research Funding; Celgene: Research Funding; AB science: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Alexion: Research Funding.
- Published
- 2016
43. A new recurrent translocation t(11;14)(q24;q32) involving IGH@ and miR-125b-1 in B-cell progenitor acute lymphoblastic leukemia
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Isabelle Radford-Weiss, Julie Lachenaud, Pierre Brousset, Florence Nguyen-Khac, Stéphanie Struski, Christine J. Harrison, Hélène Cavé, Olivier Bernard, Véronique Della Valle, Elise Chapiro, and Lisa J. Russell
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Molecular Sequence Data ,Chromosomal translocation ,Biology ,Translocation, Genetic ,immune system diseases ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Sequence Homology, Nucleic Acid ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,In Situ Hybridization, Fluorescence ,B cell ,Progenitor ,Chromosomes, Human, Pair 14 ,Hematology ,Base Sequence ,Chromosomes, Human, Pair 11 ,Cancer ,hemic and immune systems ,Gene rearrangement ,Middle Aged ,medicine.disease ,MicroRNAs ,medicine.anatomical_structure ,Oncology ,Karyotyping ,Immunology ,Cancer research ,Immunoglobulin heavy chain ,Female ,Stem cell ,Immunoglobulin Heavy Chains - Abstract
A new recurrent translocation t(11;14)(q24;q32) involving IGH@ and miR-125b-1 in B-cell progenitor acute lymphoblastic leukemia
- Published
- 2010
44. A Mendelian predisposition to B-cell lymphoma caused by IL-10R deficiency
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Frank M. Ruemmele, Patrick Nitschke, Frederic Davi, Danielle Canioni, Alain Fischer, Olivier Goulet, Julie Bruneau, Capucine Picard, Bertrand Nadel, Frédéric Rieux-Laucat, Katy Billot, Christine Bole, Daniel Kotlarz, Sophie Kaltenbach, Stéphane Blanche, Dhaarini Murugan, Pierre Frange, Emilie Mamessier, Vahid Asnafi, Isabelle Radford-Weiss, Felipe Suarez, Julien Masliah-Planchon, Véronique Baud, Jean-Laurent Casanova, Olivier Hermine, Christoph Klein, Bénédicte Neven, Nicole Brousse, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), 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), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Assistance Publique-Hôpitaux de Paris, Service d'Immunologie et d'Hématologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Unité de recherche Plantes et Systèmes de Culture Horticoles (PSH), Institut National de la Recherche Agronomique (INRA), Developpement Normal et Pathologique du Système Immunitaire, Service d'anatomie pathologique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Laboratoire de Probabilités et Modèles Aléatoires (LPMA), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Pierre et Marie Curie - Paris 6 (UPMC), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], and CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
- Subjects
Male ,Interleukin-10 Receptor alpha Subunit ,Biochemistry ,Inflammatory bowel disease ,0302 clinical medicine ,Age of Onset ,Child ,B-cell lymphoma ,Receptor ,ComputingMilieux_MISCELLANEOUS ,0303 health sciences ,NF-kappa B ,Hematology ,Interleukin-10 ,Pedigree ,3. Good health ,Interleukin 10 ,Child, Preschool ,030220 oncology & carcinogenesis ,symbols ,Female ,Lymphoma, Large B-Cell, Diffuse ,medicine.symptom ,Signal Transduction ,Lymphoma, B-Cell ,Adolescent ,Immunology ,Inflammation ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,03 medical and health sciences ,symbols.namesake ,medicine ,Humans ,Genetic Predisposition to Disease ,Microbiome ,030304 developmental biology ,business.industry ,Gene Expression Profiling ,Cell Biology ,[SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy ,Germinal Center ,Inflammatory Bowel Diseases ,Interleukin-10 Receptor beta Subunit ,medicine.disease ,Lymphoma ,Mutation ,Mendelian inheritance ,Genes, rel ,business - Abstract
Monogenic interleukin-10 (IL-10) and IL-10 receptor (IL-10R) deficiencies cause very early onset severe inflammatory bowel disease. Here, we report that 5 patients with an IL-10R1 (n = 1) or IL-10R2 (n = 4) deficiency developed B-cell non-Hodgkin lymphoma between the ages of 5 and 6 years (which was recurrent in 1 patient). These lymphomas had some of the characteristics of diffuse large B-cell lymphomas and contained monoclonal, Epstein-Barr virus-negative germinal center B cells. The tumors displayed a remarkably homogeneous signature, with original activation of the nuclear factor κB pathway and a decrease in intratumor T-cell infiltration. Hence, IL-10R deficiency is associated with a high risk of developing B-cell lymphoma. Our results revealed an unexpected role of the IL-10R pathway in lymphomagenesis.
- Published
- 2013
45. LRRFIP1, a new FGFR1 partner gene associated with 8p11 myeloproliferative syndrome
- Author
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Sylvie Nusbaum, S. Romana, Michel Vekemans, Elisabeth Macintyre, Gwendoline Soler, Bruno Varet, and Isabelle Radford-Weiss
- Subjects
Genetics ,Cancer Research ,Oncology ,Fibroblast growth factor receptor 1 ,Karyotype ,Base sequence ,Hematology ,Biology ,8p11 Myeloproliferative Syndrome ,Peptide sequence ,Gene - Published
- 2009
46. Fluorescence In Situ Hybridization Analysis of Masked (8;21)(q22;q22) Translocations
- Author
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Isabelle Radford-Weiss, Michel Vekemans, Christine J. Harrison, Fiona M. Ross, Katrina Rack, Gaëlle Le Guyader, and Elizabeth Macintyre
- Subjects
Adult ,Male ,Cancer Research ,Acute myeloblastic leukemia ,Chromosomes, Human, Pair 21 ,Chromosomal translocation ,Chromosomal rearrangement ,Biology ,Fusion gene ,hemic and lymphatic diseases ,Complex Karyotype ,Genetics ,medicine ,Humans ,Child ,neoplasms ,Molecular Biology ,Metaphase ,In Situ Hybridization, Fluorescence ,medicine.diagnostic_test ,Reverse Transcriptase Polymerase Chain Reaction ,Karyotype ,medicine.disease ,Molecular biology ,Leukemia, Myeloid, Acute ,Karyotyping ,Female ,Chromosomes, Human, Pair 8 ,Fluorescence in situ hybridization - Abstract
The translocation (8;21)(q22;q22) is associated with acute myeloblastic leukemia (AML M2). The accurate detection of this chromosomal rearrangement is vital due to its association with a favorable prognosis. Variant translocations exist; these may be hidden within an unusual or complex karyotype. In such cases, it is often difficult to confirm the presence of t(8;21)(q22;q22) by conventional cytogenetic analysis alone. The molecular detection of the AML1/ETO fusion gene is possible by reverse transcriptase polymerase chain reaction (RT-PCR) or dual-color fluorescence in situ hybridization (FISH) using probes specific for AML1 and ETO. Four cases of AML M2, with unusual or complex structural chromosomal abnormalities, without cytogenetic evidence of the classical t(8;21)(q22;q22), were studied by FISH. Two were AML1/ETO positive by RT-PCR, one showed a rearrangement by AML1 by Southern analysis, and the fourth had morphological features characteristic of t(8;21). The FISH results showed a co-localization of one AML1 and one ETO signal in interphase and metaphase nuclei in all four cases, demonstrating the presence of variant t(8;21)(q22;q22) rearrangements. Therefore, FISH analysis with the AML1 and ETO probes is extremely valuable, in cases of AML M2, because of its ability to reveal masked t(8;21)(q22;q22) translocations and thus quickly confirm the diagnosis, allowing patients to be assigned to the correct risk group in terms of treatment.
- Published
- 1999
47. FISH detection of chromosome 14q32/IgH translocations: evaluation in follicular lymphoma
- Author
-
Elizabeth Macintyre, Sylvie Nusbaum, Christian Schmitt, Michel Vekemans, Florence Salomon-Nguyen, Françoise Valensi, Katrina Rack, Isabelle Radford-Weiss, Coralie Belanger, and Maria Ocana Gil
- Subjects
Genetics ,medicine.medical_specialty ,medicine.diagnostic_test ,Cytogenetics ,Follicular lymphoma ,Locus (genetics) ,Chromosomal translocation ,Hematology ,Gene rearrangement ,Biology ,medicine.disease ,Molecular biology ,Immunoglobulin class switching ,medicine ,Cosmid ,Fluorescence in situ hybridization - Abstract
A FISH strategy capable of detecting chromosome 14q32 rearrangements involving the IgH locus, including in interphase nuclei, was developed using Ig variable and constant region cosmids from the extremities of the locus in a dual hybridization approach, using signal splitting as evidence of rearrangement. The large size of the locus (1.3 Mb) and the propensity for internal deletion due to physiological VDJ recombination and isotype switching complicate analysis of this locus. We used the Ig10 cosmid, which hybridizes to C epsilon and C alpha2 at the 3' end of the constant region, in order to minimize deletion and/or splitting of the constant region probe. Cos Ig10 and the IgV18 VH probes were compared with a specific IgH-BCL2 FISH dual hybridization approach in follicular lymphoma (FL). Both were capable of detecting the t(14;18) in interphase nuclei, including in cases with no apparent abnormality by classic karyotype analysis, although the sensitivity of the IgH approach was slightly lower. We have also successfully applied these probes to whole cell cytospin preparations, rendering analysis of cryopreserved material possible, although interpretation should be limited to frequent events, particularly following cell manipulation. Analysis of flow cytometric sorted bone marrow fractions from three FL patients by FISH and FICTION showed that the t(14;18) was present in a much lower proportion of CD34 positive than negative cells but that the higher level of background hybridization limits use of these techniques for the reliable quantification of rare events.
- Published
- 1998
48. Simultaneous detection ofMYC,BVR1, andPVT1 translocations in lymphoid malignancies by fluorescence in situ hybridization
- Author
-
Eric Delabesse, Elizabeth Macintyre, Isabelle Radford-Weiss, Priscille Bourquelot, Katrina Rack, Gaëlle Le Guyader, and Michel Vekemans
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,medicine.diagnostic_test ,Breakpoint ,Chromosomal translocation ,Locus (genetics) ,Biology ,Molecular biology ,Rapid detection ,PVT1 ,Chromosome Band ,hemic and lymphatic diseases ,Genetics ,medicine ,Interphase ,Fluorescence in situ hybridization - Abstract
The rapid detection of chromosome band 8q24 rearrangements, including classical translocations involving MYC and variant 3' translocations, is important for the accurate diagnosis and appropriate treatment of lymphoid malignancies. We have identified and characterized a CEPH YAC, 934e1, which extends from at least 190 kbp upstream to over 280 kbp downstream to MYC, allowing detection of classical t(8; 14)(q24;q32) and variant t(8;22)(q24;q11) and t(8;14)(q24;q11), extending distal to PVT1 and therefore, by extrapolation, to BVR1. This YAC also allowed clarification of complex chromosome 8 abnormalities and the identification of translocations in interphase nuclei. A second CEPH YAC, 904c3, previously shown to contain the PVT1 locus but not MYC, allowed distinction between translocations occurring centromeric and telomeric to MYC. Use of the 934e1 YAC will aid classification of a variety of lymphoid proliferations and further characterization of rearranged cases with the 904c3 YAC will simplify mapping of their diverse breakpoints.
- Published
- 1998
49. Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia
- Author
-
Isabelle Radford-Weiss, Eric Delabesse, Marianne Debré, Elizabeth Macintyre, Virginie Penard-Lacronique, Jean-Luc Villeval, Roland Berger, William Vainchenker, Sébastien Malinge, Catherine Settegrana, Kheira Beldjord, Olivier Bernard, and Raouf Ben-Abdelali
- Subjects
Cellular differentiation ,Molecular Sequence Data ,Immunology ,Gene mutation ,Biochemistry ,Mice ,Cell Line, Tumor ,Acute lymphocytic leukemia ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Conserved Sequence ,B cell ,Regulation of gene expression ,B-Lymphocytes ,Acute leukemia ,Janus kinase 2 ,Base Sequence ,biology ,Cell Differentiation ,Cell Biology ,Hematology ,Janus Kinase 2 ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Enzyme Activation ,medicine.anatomical_structure ,Child, Preschool ,Mutation ,biology.protein ,Cancer research ,Down Syndrome ,Sequence Alignment ,Tyrosine kinase - Abstract
Activation of tyrosine kinase genes is a frequent event in human hematologic malignancies. Because gene activation could be associated with gene dysregulation, we attempted to screen for activating gene mutation based on high-level gene expression. We focused our study on the Janus kinase 2 (JAK2) gene in 90 cases of acute leukemia. This strategy led to the identification of a novel JAK2-acquired mutation in a patient with Down syndrome (DS) with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This mutation involves a 5–amino acid deletion within the JH2 pseudokinase domain (JAK2ΔIREED). Expression of JAK2ΔIREED in Ba/F3 cells induced constitutive activation of the JAK-STAT pathway and growth factor–independent cell proliferation. These results highlight the JAK2 pseudokinase domain as an oncogenic hot spot and indicate that activation of the JAK-STAT pathway may contribute to lymphoid malignancies and hematologic disorders observed in children with DS.
- Published
- 2006
50. Acute megakaryoblastic leukemia and loss of the RUNX1 gene
- Author
-
Anne Hagemeijer, Maryvonne Busson, Laurence Benattar, Benoît Quilichini, Isabelle Radford-Weiss, Roland Berger, Lucienne Michaux, Olivier Bernard, Nicole Dastugue, and Serge Romana
- Subjects
Adult ,Male ,Cancer Research ,Biology ,Acute megakaryoblastic leukemia ,chemistry.chemical_compound ,Leukemia, Megakaryoblastic, Acute ,hemic and lymphatic diseases ,Genetics ,medicine ,Numerical Chromosome Anomaly ,Humans ,Molecular Biology ,Gene ,Aged ,Megakaryopoiesis ,medicine.diagnostic_test ,Infant, Newborn ,Infant ,Middle Aged ,medicine.disease ,RUNX1 ,chemistry ,Child, Preschool ,Core Binding Factor Alpha 2 Subunit ,embryonic structures ,Cancer research ,Female ,Trisomy ,Haploinsufficiency ,Gene Deletion ,Fluorescence in situ hybridization - Abstract
Since the RUNX1 gene contributes to megakaryopoiesis and acquired trisomy 21 is the most frequent numerical chromosome anomaly in acute megakaryoblastic leukemia (AMLK), a systematic study of RUNX1 abnormalities was performed by fluorescence in situ hybridization in AMLK patients. Four abnormalities were detected among 15 patients. One copy of RUNX1 was completeley or partially lost in three patients and translocated onto Xq24 in the fourth. The possible consequences of RUNX1 haploinsufficiency are discussed. (c) 2006 Elsevier Inc. All rights reserved.
- Published
- 2006
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