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1. Exploration of nuclear body-enhanced sumoylation reveals that PML represses 2-cell features of embryonic stem cells

Author: Sarah Tessier, Omar Ferhi, Marie-Claude Geoffroy, Román González-Prieto, Antoine Canat, Samuel Quentin, Marika Pla, Michiko Niwa-Kawakita, Pierre Bercier, Domitille Rérolle, Pierre Therizols, Emmanuelle Fabre, Alfred C. O. Vertegaal, Hugues de Thé, and Valérie Lallemand-Breitenbach
Subjects: Science
Abstract: Here the authors identify novel PML-partners and demonstrate that PML NBs control their sumoylation and that PML-controlled sumoylation of transcriptional regulators maintains the embryonic stem cell transcriptome and transposable element silencing.
Published: 2022
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2. Author Correction: Exploration of nuclear body-enhanced sumoylation reveals that PML represses 2-cell features of embryonic stem cells

Author: Sarah Tessier, Omar Ferhi, Marie-Claude Geoffroy, Román González-Prieto, Antoine Canat, Samuel Quentin, Marika Pla, Michiko Niwa-Kawakita, Pierre Bercier, Domitille Rérolle, Marilyn Tirard, Pierre Therizols, Emmanuelle Fabre, Alfred C. O. Vertegaal, Hugues de Thé, and Valérie Lallemand-Breitenbach
Subjects: Science
Published: 2023
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3. Key Resources Table from Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy

Author: Hugues de Thé, Maria Paola Martelli, Keisuke Ito, Brunangelo Falini, Ali Bazarbachi, Valérie Lallemand-Breitenbach, Tak W. Mak, Lorenzo Brunetti, Guido Kroemer, Olivier Espeli, Pierre Fenaux, Hervé Dombret, Raphael Itzykson, Lionel Ades, Emmanuel Raffoux, Hiba El Hajj, Pierre Rustin, Paule Bénit, Jennifer J. Trowbridge, Sylvère Durand, Jean Soulier, Stéphanie Gachet, Sylvie Souquere, Emmanuelle Clappier, Marie Sebert, Sylvie Rimsky, Lidio Conte, Chengchen Wu, Claudia Morganti, Shirine Benhenda, Samuel Quentin, Takashi Sakamoto, Rita Hleihel, Caroline Berthier, Domitille Rérolle, and Hsin-Chieh Wu
Abstract: Key resource table with RRID
Published: 2023
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4. Table S3 from Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy

Author: Hugues de Thé, Maria Paola Martelli, Keisuke Ito, Brunangelo Falini, Ali Bazarbachi, Valérie Lallemand-Breitenbach, Tak W. Mak, Lorenzo Brunetti, Guido Kroemer, Olivier Espeli, Pierre Fenaux, Hervé Dombret, Raphael Itzykson, Lionel Ades, Emmanuel Raffoux, Hiba El Hajj, Pierre Rustin, Paule Bénit, Jennifer J. Trowbridge, Sylvère Durand, Jean Soulier, Stéphanie Gachet, Sylvie Souquere, Emmanuelle Clappier, Marie Sebert, Sylvie Rimsky, Lidio Conte, Chengchen Wu, Claudia Morganti, Shirine Benhenda, Samuel Quentin, Takashi Sakamoto, Rita Hleihel, Caroline Berthier, Domitille Rérolle, and Hsin-Chieh Wu
Abstract: Supplementary table S3
Published: 2023
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5. Table S3 from Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation

Author: Jean Soulier, François Sigaux, Hugues de Thé, Claude Gazin, Jean-Jacques Diaz, Emmanuelle Clappier, Hervé Dombret, André Baruchel, Jules P. Meijerink, Pieter Van Vlierberghe, Tom Taghon, Isabelle André-Schmutz, Gerben Menschaert, Wouter Van Loocke, Jessica G. Buijs-Gladdines, Willem K. Smits, Marika Pla, Lucie Hernandez, Godelieve Meunier, Delphine Briot, Gabriel Thérizols, Marc Delord, Samuel Quentin, Frédéric Catez, Eulalia Genesca, David Avran, Tiama El-Chaar, and Stéphanie Gachet
Abstract: Differentially Expressed Proteins Deleted versus non-deleted clones
Published: 2023
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6. Data from Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy

Author: Hugues de Thé, Maria Paola Martelli, Keisuke Ito, Brunangelo Falini, Ali Bazarbachi, Valérie Lallemand-Breitenbach, Tak W. Mak, Lorenzo Brunetti, Guido Kroemer, Olivier Espeli, Pierre Fenaux, Hervé Dombret, Raphael Itzykson, Lionel Ades, Emmanuel Raffoux, Hiba El Hajj, Pierre Rustin, Paule Bénit, Jennifer J. Trowbridge, Sylvère Durand, Jean Soulier, Stéphanie Gachet, Sylvie Souquere, Emmanuelle Clappier, Marie Sebert, Sylvie Rimsky, Lidio Conte, Chengchen Wu, Claudia Morganti, Shirine Benhenda, Samuel Quentin, Takashi Sakamoto, Rita Hleihel, Caroline Berthier, Domitille Rérolle, and Hsin-Chieh Wu
Abstract: Acute myeloid leukemia (AML) pathogenesis often involves a mutation in the NPM1 nucleolar chaperone, but the bases for its transforming properties and overall association with favorable therapeutic responses remain incompletely understood. Here we demonstrate that an oncogenic mutant form of NPM1 (NPM1c) impairs mitochondrial function. NPM1c also hampers formation of promyelocytic leukemia (PML) nuclear bodies (NB), which are regulators of mitochondrial fitness and key senescence effectors. Actinomycin D (ActD), an antibiotic with unambiguous clinical efficacy in relapsed/refractory NPM1c-AMLs, targets these primed mitochondria, releasing mitochondrial DNA, activating cyclic GMP-AMP synthase signaling, and boosting reactive oxygen species (ROS) production. The latter restore PML NB formation to drive TP53 activation and senescence of NPM1c-AML cells. In several models, dual targeting of mitochondria by venetoclax and ActD synergized to clear AML and prolong survival through targeting of PML. Our studies reveal an unexpected role for mitochondria downstream of NPM1c and implicate a mitochondrial/ROS/PML/TP53 senescence pathway as an effector of ActD-based therapies.Significance:ActD induces complete remissions in NPM1-mutant AMLs. We found that NPM1c affects mitochondrial biogenesis and PML NBs. ActD targets mitochondria, yielding ROS which enforce PML NB biogenesis and restore senescence. Dual targeting of mitochondria with ActD and venetoclax sharply potentiates their anti-AML activities in vivo.This article is highlighted in the In This Issue feature, p. 2945
Published: 2023
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7. Supplementary Data from Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation

Author: Jean Soulier, François Sigaux, Hugues de Thé, Claude Gazin, Jean-Jacques Diaz, Emmanuelle Clappier, Hervé Dombret, André Baruchel, Jules P. Meijerink, Pieter Van Vlierberghe, Tom Taghon, Isabelle André-Schmutz, Gerben Menschaert, Wouter Van Loocke, Jessica G. Buijs-Gladdines, Willem K. Smits, Marika Pla, Lucie Hernandez, Godelieve Meunier, Delphine Briot, Gabriel Thérizols, Marc Delord, Samuel Quentin, Frédéric Catez, Eulalia Genesca, David Avran, Tiama El-Chaar, and Stéphanie Gachet
Abstract: Supp Fig. S1-6, Supp Tables S1-S3, Supp Methods and References
Published: 2023
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8. Supplementary Figures and Methods from Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy

Author: Hugues de Thé, Maria Paola Martelli, Keisuke Ito, Brunangelo Falini, Ali Bazarbachi, Valérie Lallemand-Breitenbach, Tak W. Mak, Lorenzo Brunetti, Guido Kroemer, Olivier Espeli, Pierre Fenaux, Hervé Dombret, Raphael Itzykson, Lionel Ades, Emmanuel Raffoux, Hiba El Hajj, Pierre Rustin, Paule Bénit, Jennifer J. Trowbridge, Sylvère Durand, Jean Soulier, Stéphanie Gachet, Sylvie Souquere, Emmanuelle Clappier, Marie Sebert, Sylvie Rimsky, Lidio Conte, Chengchen Wu, Claudia Morganti, Shirine Benhenda, Samuel Quentin, Takashi Sakamoto, Rita Hleihel, Caroline Berthier, Domitille Rérolle, and Hsin-Chieh Wu
Abstract: Supplementary figures and methods
Published: 2023
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9. Data from Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation

Author: Jean Soulier, François Sigaux, Hugues de Thé, Claude Gazin, Jean-Jacques Diaz, Emmanuelle Clappier, Hervé Dombret, André Baruchel, Jules P. Meijerink, Pieter Van Vlierberghe, Tom Taghon, Isabelle André-Schmutz, Gerben Menschaert, Wouter Van Loocke, Jessica G. Buijs-Gladdines, Willem K. Smits, Marika Pla, Lucie Hernandez, Godelieve Meunier, Delphine Briot, Gabriel Thérizols, Marc Delord, Samuel Quentin, Frédéric Catez, Eulalia Genesca, David Avran, Tiama El-Chaar, and Stéphanie Gachet
Abstract: Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14, SYNCRIP (encoding hnRNP-Q) and SNHG5 (that hosts snoRNAs), both involved in regulating RNA maturation and translation. Combined silencing of both genes, but not of either gene alone, accelerated leukemogeneis in a Tal1/Lmo1/Notch1-driven mouse model, demonstrating the tumor-suppressive nature of the two-gene region. Proteomic and translational profiling of cells in which we engineered a short 6q deletion by CRISPR/Cas9 genome editing indicated decreased ribosome and mitochondrial activities, suggesting that the resulting metabolic changes may regulate tumor progression. Indeed, xenograft experiments showed an increased leukemia-initiating cell activity of primary human leukemic cells upon coextinction of SYNCRIP and SNHG5. Our findings not only elucidate the nature of 6q deletion but also highlight the role of ribosomes and mitochondria in T-ALL tumor progression.Significance:The oncogenic role of 6q deletion in T-ALL has remained elusive since this chromosomal abnormality was first identified more than 40 years ago. We combined genomic analysis and functional models to show that the codeletion of two contiguous genes at 6q14 enhances malignancy through deregulation of a ribosome–mitochondria axis, suggesting the potential for therapeutic intervention.This article is highlighted in the In This Issue feature, p. 1494
Published: 2023
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10. Concurrent CDX2 cis-deregulation and UBTF::ATXN7L3 fusion define a novel high-risk subtype of B-cell ALL

Author: Marie Passet, Rathana Kim, Stéphanie Gachet, François Sigaux, Julie Chaumeil, Ava Galland, Thomas Sexton, Samuel Quentin, Lucie Hernandez, Lise Larcher, Hugo Bergugnat, Tao Ye, Nezih Karasu, Aurélie Caye, Beate Heizmann, Isabelle Duluc, Patrice Chevallier, Philippe Rousselot, Françoise Huguet, Thibaut Leguay, Mathilde Hunault, Françoise Pflumio, Jean-Noël Freund, Camille Lobry, Véronique Lhéritier, Hervé Dombret, Claire Domon-Dell, Jean Soulier, Nicolas Boissel, and Emmanuelle Clappier
Subjects: Immunology, Cell Biology, Hematology, Biochemistry
Abstract: Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA sequencing and whole-genome analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of 2 genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTF::ATXN7L3 fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cis from the deletion. Using 4C-sequencing and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3 enhancer hijacking. CDX2/UBTF ALL (n = 26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4 activating mutations. Within adult patients with Ph− B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n = 17/723, 2.4%) were young (median age, 31 years) and dramatically enriched in females (male/female ratio, 0.2, P = .002). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% vs 3%, P = .017) and higher post-induction minimal residual disease (MRD) levels (MRD ≥ 10−4, 93% vs 46%, P < .001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% vs 32.4%, P = .004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTF::ATXN7L3 fusion, representing a high-risk disease in young adults.
Published: 2022
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11. Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia

Author: Marie Sebert, Stéphanie Gachet, Thierry Leblanc, Alix Rousseau, Olivier Bluteau, Rathana Kim, Raouf Ben Abdelali, Flore Sicre de Fontbrune, Loïc Maillard, Carèle Fedronie, Valentine Murigneux, Léa Bellenger, Naira Naouar, Samuel Quentin, Lucie Hernandez, Nadia Vasquez, Mélanie Da Costa, Pedro H. Prata, Lise Larcher, Marie de Tersant, Matthieu Duchmann, Anna Raimbault, Franck Trimoreau, Odile Fenneteau, Wendy Cuccuini, Nathalie Gachard, Nathalie Auger, Giulia Tueur, Maud Blanluet, Claude Gazin, Michèle Souyri, Francina Langa Vives, Aaron Mendez-Bermudez, Hélène Lapillonne, Etienne Lengline, Emmanuel Raffoux, Pierre Fenaux, Lionel Adès, Edouard Forcade, Charlotte Jubert, Carine Domenech, Marion Strullu, Bénédicte Bruno, Nimrod Buchbinder, Caroline Thomas, Arnaud Petit, Guy Leverger, Gérard Michel, Marina Cavazzana, Eliane Gluckman, Yves Bertrand, Nicolas Boissel, André Baruchel, Jean-Hugues Dalle, Emmanuelle Clappier, Eric Gilson, Ludovic Deriano, Sylvie Chevret, François Sigaux, Gérard Socié, Dominique Stoppa-Lyonnet, Hugues de Thé, Christophe Antoniewski, Dominique Bluteau, Régis Peffault de Latour, Jean Soulier, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), AP-HP Hôpital universitaire Robert-Debré [Paris], Recherche clinique appliquée à l'hématologie (URP_3518), Intégrité du génome, immunité et cancer - Genome integrity, Immunity and Cancer, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Limoges, Institut Gustave Roussy (IGR), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Institut Pasteur [Paris] (IP), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), CHU Nice [Cimiez], Hôpital Cimiez [Nice] (CHU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpitaux universitaires Est parisien [AP-HP], CHU Bordeaux [Bordeaux], Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Rouen, Normandie Université (NU), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix Marseille Université (AMU), Hôpital de la Timone [CHU - APHM] (TIMONE), CIC NECKER BT (CIC 1416), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Collège de France (CdF (institution)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), This study received support from the European Research Council (ERC) Consolidator Grant to J.S. (CEVAL-311660), the FP7 Eurofancolen program (HEALTH-F5-2012-305421), the ANR program PACRI (Projet alliance parisienne des instituts de recherche en cancérologie), the CONECT-AML (Collaborative Network for Children and Teenagers with Acute Myeloid Leukemia) program supported by a grant from the Institut National du Cancer (INCa), Fondation ARC, Ligue nationale contre le cancer, and Laurette Fugain (INCa-ARC-LIGUE_11905) to J.S. and C.A., and the Association Française pour la Maladie de Fanconi (AFMF) grants 'Histoire naturelle de la maladie de Fanconi' to R.P.L. and J.S., 'Modélisation de la transformation leucémique dans la maladie de Fanconi' to D.B., and 'Cribles fonctionnels à haut débit de gènes modificateurs de la maladie de Fanconi' to C.G. M.S. was supported by the AVIESAN-INCa Program 'Formation à la Recherche Translationnelle,' and A.R. by a grant from the Fondation ARC. The work in E.G.’s lab is supported by Fondation ARC and ANR Telochrom. The work in L.D.’s lab is supported by INCa (PLBIO16-181) and ERC (310917)., ANR-11-PHUC-0002,PACRI,Alliance Parisienne des Instituts de Recherche en Cancérologie(2011), European Project: 311660,EC:FP7:ERC,ERC-2012-StG_20111109,CEVAL(2013), and European Project: 305421,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,EUROFANCOLEN(2013)
Subjects: MDM4, Fanconi anemia, precision medicine, [SDV]Life Sciences [q-bio], Genetics, leukemia, clonal hematopoiesis, Molecular Medicine, Cell Biology, TP53, mutational signature, genomic instability, BRCA2
Abstract: International audience; Fanconi anemia (FA) patients experience chromosome instability, yielding hematopoietic stem/progenitor cell (HSPC) exhaustion and predisposition to poor-prognosis myeloid leukemia. Based on a longitudinal cohort of 335 patients, we performed clinical, genomic, and functional studies in 62 patients with clonal evolution. We found a unique pattern of somatic structural variants and mutations that shares features of BRCA-related cancers, the FA-hallmark being unbalanced, microhomology-mediated translocations driving copy-number alterations. Half the patients developed chromosome 1q gain, driving clonal hematopoiesis through MDM4 trisomy downmodulating p53 signaling later followed by secondary acute myeloid lukemia genomic alterations. Functionally, MDM4 triplication conferred greater fitness to murine and human primary FA HSPCs, rescued inflammation-mediated bone marrow failure, and drove clonal dominance in FA mouse models, while targeting MDM4 impaired leukemia cells in vitro and in vivo. Our results identify a linear route toward secondary leukemogenesis whereby early MDM4-driven downregulation of basal p53 activation plays a pivotal role, opening monitoring and therapeutic prospects.
Published: 2023
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12. Clonal dominance is an adverse prognostic factor in acute myeloid leukemia treated with intensive chemotherapy

Author: François Delhommeau, Ramy Rahmé, Nicolas Boissel, Pierre Sujobert, Marie Sebert, Emmanuelle Clappier, Raphael Itzykson, Anna Raimbault, Matthieu Duchmann, Samuel Quentin, Nathalie Dhedin, Florence Rabian, Xavier Thomas, Jean Soulier, Odile Maarek, Etienne Lengliné, Emmanuel Raffoux, Loic Vasseur, Pierre Fenaux, Rathana Kim, Marco Cerrano, Marie Passet, Justine Pasanisi, Lionel Ades, Hervé Dombret, Pierre Hirsch, and Karine Celli-Lebras
Subjects: 0301 basic medicine, Oncology, Cancer Research, Prognostic factor, Chemotherapy, medicine.medical_specialty, medicine.medical_treatment, Myeloid leukemia, Hematology, Biology, Phenotype, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, Cohort, medicine, Genotyping, Exome sequencing, Dominance (genetics)
Abstract: Intra-tumor heterogeneity portends poor outcome in many cancers. In AML, a higher number of drivers worsens prognosis. The Shannon Index is a robust metric of clonal heterogeneity that accounts for the number of clones, but also their relative abundance. We show that a Shannon Index can be estimated from bulk sequencing, which is correlated (ρ = 0.76) with clonal diversity from single-colony genotyping. In a discovery cohort of 292 patients with sequencing of 43 genes, a higher number of drivers (HR = 1.18, P = 0.028) and a lower Shannon Index (HR = 0.68, P = 0.048), the latter reflecting clonal dominance, are independently associated with worse OS independently of European LeukemiaNet 2017 risk. These findings are validated in an independent cohort of 1184 patients with 111-gene sequencing (number of drivers HR = 1.16, P = 1 × 10−5, Shannon Index HR = 0.81, P = 0.007). By re-interrogating paired diagnosis/relapse exomes from 50 cytogenetically normal AMLs, we find clonal dominance at diagnosis to be correlated with the gain of a significantly higher number of mutations at relapse (P = 6 × 10−6), hence with clonal sweeping. Our results suggest that clonal dominance at diagnosis is associated with the presence of a leukemic phenotype allowing rapid expansion of new clones and driving relapse after chemotherapy.
Published: 2020
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13. Germline DDX41 mutations define a significant entity within adult MDS/AML patients

Author: Jean Soulier, Mélanie Da Costa, Hervé Dombret, Marco Cerrano, Anna Raimbault, Gérard Socié, Nadia Vasquez, Lionel Ades, Marie Passet, Ramy Rahmé, Flore Sicre de Fontbrune, Marie Sebert, Raphael Itzykson, Emmanuel Raffoux, Pierre Fenaux, Emmanuelle Clappier, Régis Peffault de Latour, Samuel Quentin, and Nicolas Boissel
Subjects: Adult, Male, Oncology, medicine.medical_specialty, Myeloid, Immunology, Azacitidine, Biochemistry, Germline, Cohort Studies, DEAD-box RNA Helicases, Germline mutation, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Family history, Germ-Line Mutation, Aged, Aged, 80 and over, Cytopenia, business.industry, Myelodysplastic syndromes, Cell Biology, Hematology, Middle Aged, medicine.disease, Leukemia, Myeloid, Acute, Leukemia, medicine.anatomical_structure, Myelodysplastic Syndromes, Female, business, medicine.drug
Abstract: Germline DDX41 mutations are involved in familial myelodysplastic syndromes (MDSs) and acute myeloid leukemias (AMLs). We analyzed the prevalence and characteristics of DDX41-related myeloid malignancies in an unselected cohort of 1385 patients with MDS or AML. Using targeted next-generation sequencing, we identified 28 different germline DDX41 variants in 43 unrelated patients, which we classified as causal (n = 21) or unknown significance (n = 7) variants. We focused on the 33 patients having causal variants, representing 2.4% of our cohort. The median age was 69 years; most patients were men (79%). Only 9 patients (27%) had a family history of hematological malignancy, and 15 (46%) had a personal history of cytopenia years before MDS/AML diagnosis. Most patients had a normal karyotype (85%), and the most frequent somatic alteration was a second DDX41 mutation (79%). High-risk DDX41 MDS/AML patients treated with intensive chemotherapy (n = 9) or azacitidine (n = 11) had an overall response rate of 100% or 73%, respectively, with a median overall survival of 5.2 years. Our study highlights that germline DDX41 mutations are relatively common in adult MDS/AML, often without known family history, arguing for systematic screening. Salient features of DDX41-related myeloid malignancies include male preponderance, frequent preexisting cytopenia, additional somatic DDX41 mutation, and relatively good outcome.
Published: 2019
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14. PAX5 P80R mutation identifies a novel subtype of B-cell precursor acute lymphoblastic leukemia with favorable outcome

Author: Yves Chalandon, Véronique Lhéritier, Hervé Dombret, Johanna Konopacki, Eric Delabesse, Nicolas Boissel, Carlos Graux, Marie Passet, Colombe Saillard, Vahid Asnafi, Nathalie Grardel, Jean Soulier, Mario Bargetzi, Thibaut Leguay, Samuel Quentin, Emmanuelle Clappier, Ibrahima Ba, Marina Lafage-Pochitaloff, Xavier Thomas, Cedric Pastoret, François Sigaux, and Etienne Lengliné
Subjects: Adult, Homologous, 0301 basic medicine, Immunology, Chromosomal translocation, Malignancy, medicine.disease_cause, PAX5 Transcription Factor/genetics, Biochemistry, Cohort Studies, Fusion gene, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Acute lymphocytic leukemia, Local/genetics/pathology/therapy, medicine, Humans, B cell, ddc:616, Transplantation, Mutation, business.industry, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/classification/genetics/pathology/therapy, Cell Biology, Hematology, Prognosis, medicine.disease, Survival Rate, Neoplasm Recurrence, 030104 developmental biology, medicine.anatomical_structure, Cancer research, PAX5, business, Follow-Up Studies, Stem Cell Transplantation, 030215 immunology
Abstract: TO THE EDITOR: B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a rare aggressive malignancy in adults. BCP-ALL is frequently characterized by recurrent chromosomal translocations that deregulate proto-oncogenes or result in fusion genes encoding chimeric oncoproteins.[1][1] Gene
Published: 2019
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15. Unbiased in vivo exploration of nuclear bodies-enhanced sumoylation reveals that PML orchestrates embryonic stem cell fate

Author: Marie-Claude Geoffroy, Sarah Tessier, Domitille Rérolle, Alfred C.O. Vertegaal, Pierre Bercier, Marika Pla, Román González-Prieto, Omar Ferhi, Emmanuelle Fabre, Valérie Lallemand-Breitenbach, Antoine Canat, Samuel Quentin, Pierre Therizols, Michiko Niwa-Kawakita, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Leiden University Medical Center (LUMC), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Therizols, Pierre
Subjects: Senescence, viruses, [SDV]Life Sciences [q-bio], SUMO protein, Repressor, 2-cell-like cells, SUMO2, Biology, Proteomics, stress, 03 medical and health sciences, 0302 clinical medicine, Cancer stem cell, Epigenetics, 030304 developmental biology, 0303 health sciences, sumoylation, arsenic, virus diseases, PML nuclear bodies, embryonic stem cells, acute promyelocytic leukemia, Embryonic stem cell, Cell biology, [SDV] Life Sciences [q-bio], KAP1-TRIM28-TIF1b, transposable elements, DPPA2, epigenetic, 030217 neurology & neurosurgery
Abstract: SummaryMembrane-less organelles are condensates formed by phase separation whose functions often remain enigmatic. Upon oxidative stress, PML scaffolds Nuclear Bodies (NBs) to regulate senescence or metabolic adaptation, but their role in pluripotency remains elusive. Here we establish that PML is required for basal SUMO2/3 conjugation in mESCs and oxidative stress-driven sumoylation in mESCs or in vivo. PML NBs create an oxidation-protective environment for UBC9-driven SUMO2/3 conjugation of PML partners, often followed by their poly-ubiquitination and degradation. Differential in vivo proteomics identified several members of the KAP1 complex as PML NB-dependent SUMO2-targets. The latter drives functional activation of this key epigenetic repressor. Accordingly, Pml−/− mESCs re-express transposable elements and display features of totipotent-like cells, a process further enforced by PML-controlled SUMO2-conjugation of DPPA2. Finally, PML is required for adaptive stress responses in mESCs. Collectively, PML orchestrates mESC fate through SUMO2-conjugation of key transcriptional or epigenetic regulators, raising new mechanistic hypotheses about PML roles in normal or cancer stem cells.
Published: 2021
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16. Exploration of nuclear body-enhanced sumoylation reveals that PML represses 2-cell features of embryonic stem cells

Author: Sarah, Tessier, Omar, Ferhi, Marie-Claude, Geoffroy, Román, González-Prieto, Antoine, Canat, Samuel, Quentin, Marika, Pla, Michiko, Niwa-Kawakita, Pierre, Bercier, Domitille, Rérolle, Pierre, Therizols, Emmanuelle, Fabre, Alfred C O, Vertegaal, Hugues, de Thé, and Valérie, Lallemand-Breitenbach
Subjects: Mice, Nuclear Bodies, DNA Transposable Elements, Animals, Sumoylation, Embryonic Stem Cells, Arsenic, Transcription Factors
Abstract: Membrane-less organelles are condensates formed by phase separation whose functions often remain enigmatic. Upon oxidative stress, PML scaffolds Nuclear Bodies (NBs) to regulate senescence or metabolic adaptation. PML NBs recruit many partner proteins, but the actual biochemical mechanism underlying their pleiotropic functions remains elusive. Similarly, PML role in embryonic stem cell (ESC) and retro-element biology is unsettled. Here we demonstrate that PML is essential for oxidative stress-driven partner SUMO2/3 conjugation in mouse ESCs (mESCs) or leukemia, a process often followed by their poly-ubiquitination and degradation. Functionally, PML is required for stress responses in mESCs. Differential proteomics unravel the KAP1 complex as a PML NB-dependent SUMO2-target in arsenic-treated APL mice or mESCs. PML-driven KAP1 sumoylation enables activation of this key epigenetic repressor implicated in retro-element silencing. Accordingly, Pml
Published: 2021

17. Actinomycin D targets NPM1c-primed mitochondria to restore PML-driven senescence in AML therapy

Author: Hsin-Chieh Wu, Domitille Rerolle, Caroline Berthier, Rita Hleihel, Takashi Sakamoto, Samuel Quentin, Shirine Benhenda, Claudia Morganti, Chengchen Wu, Lidio Conte, Sylvie Rimsky, Marie Sebert, Emmanuelle Clappier, Sylvie Souquere, Stephanie Gachet, Jean Soulier, Sylvere Durand, Jennifer J Trowbridge, Paule Benit, Pierre Rustin, Hiba El Hajj, Emmanuel Raffoux, Lionel Ades, Raphael Itzykson, Herve D
Published: 2021
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18. Clonal dominance is an adverse prognostic factor in acute myeloid leukemia treated with intensive chemotherapy

Author: Marco, Cerrano, Matthieu, Duchmann, Rathana, Kim, Loic, Vasseur, Pierre, Hirsch, Xavier, Thomas, Samuel, Quentin, Justine, Pasanisi, Marie, Passet, Florence, Rabian, Ramy, Rahmé, Etienne, Lengliné, Emmanuel, Raffoux, Nathalie, Dhédin, Marie, Sébert, Odile, Maarek, Anna, Raimbault, Karine, Celli-Lebras, Lionel, Adès, Pierre, Fenaux, Nicolas, Boissel, François, Delhommeau, Jean, Soulier, Hervé, Dombret, Emmanuelle, Clappier, Pierre, Sujobert, and Raphael, Itzykson
Subjects: Clonal Evolution, Gene Expression Regulation, Neoplastic, Male, Survival Rate, Leukemia, Myeloid, Acute, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Humans, Female, Middle Aged, Prognosis, Follow-Up Studies, Retrospective Studies
Abstract: Intra-tumor heterogeneity portends poor outcome in many cancers. In AML, a higher number of drivers worsens prognosis. The Shannon Index is a robust metric of clonal heterogeneity that accounts for the number of clones, but also their relative abundance. We show that a Shannon Index can be estimated from bulk sequencing, which is correlated (ρ = 0.76) with clonal diversity from single-colony genotyping. In a discovery cohort of 292 patients with sequencing of 43 genes, a higher number of drivers (HR = 1.18, P = 0.028) and a lower Shannon Index (HR = 0.68, P = 0.048), the latter reflecting clonal dominance, are independently associated with worse OS independently of European LeukemiaNet 2017 risk. These findings are validated in an independent cohort of 1184 patients with 111-gene sequencing (number of drivers HR = 1.16, P = 1 × 10
Published: 2019

19. Familial predisposition to TP53/complex karyotype MDS and leukemia in DNA repair-deficient xeroderma pigmentosum

Author: Nathalie Droin, Alain Sarasin, Jean-Luc Schmutz, Stéphane de Botton, Samuel Quentin, Anna Raimbault, Filippo Rosselli, Alain Taieb, Véronique Saada, Vahid Asnafi, Jean Soulier, Yannick Boursin, Philippe Dessen, Patricia Kannouche, Thierry Leblanc, Nathalie Auger, Caroline Robert, Flore Sicre de Fontbrune, Mourad Sahbatou, Laurianne Drieu La Rochelle, Marie Sebert, Carlos Frederico Martins Menck, Eric Solary, Génomes et cancer (GC (FRE2939)), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB), Fondation Jean Dausset CEPH, Laboratory of Hematology, Gustave Roussy, Villejuif, Praxiling (Praxiling), Centre National de la Recherche Scientifique (CNRS)-Université Paul-Valéry - Montpellier 3 (UPVM), Plateforme de Bioinformatique [Gustave Roussy], 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)-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), 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), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Service de Dermatologie et Allergologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Universidade de Sao Paulo, Institute of Biomedical Sciences, Universidade de São Paulo (USP)-Institute of Biomedical Sciences (ICB/USP), Universidade de São Paulo (USP), Stabilité Génétique et Oncogenèse (UMR 8200), Hematopoïèse et Cellules Souches (U362), Institut Gustave Roussy (IGR)-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), Service d'hématologie et immunologie pédiatrique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Gustave Roussy (IGR), Radiothérapie moléculaire (UMR 1030), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), 3UMR728 INSERM Unité d'immuno-hématologie (UIH) and laboratoire d'hématologie, Hôpital St-Louis, AP-HP, Centre National de la Recherche Scientifique (CNRS), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Praxiling UMR 5267 (Praxiling), Université Paul-Valéry - Montpellier 3 (UM3)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: 0301 basic medicine, Xeroderma pigmentosum, DNA repair, [SDV]Life Sciences [q-bio], Immunology, medicine.disease_cause, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Complex Karyotype, Familial predisposition, medicine, Letter to Blood, Gene, ComputingMilieux_MISCELLANEOUS, Genetics, Mutation, business.industry, Cell Biology, Hematology, medicine.disease, 3. Good health, Leukemia, 030104 developmental biology, 030220 oncology & carcinogenesis, business, Founder effect
Abstract: There is a Blood Commentary on this article in this issue.
Published: 2019
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20. Copy-number analysis identified new prognostic marker in acute myeloid leukemia

Author: Agnès Paquet, Olivier Nibourel, Soizic Guihard, C Demay, Claude Preudhomme, Karine Celli-Lebras, Pauline Peyrouze, Jean Soulier, Christophe Roumier, Aline Renneville, Raouf Ben Abdelali, Pascal Barbry, Antonio José Alberdi, Sylvie Castaigne, Christine Terré, Nicolas Pottier, Hervé Dombret, Sandrine Geffroy, Samuel Quentin, Meyling Cheok, and Bruno Quesnel
Subjects: Adult, Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Myeloid, DNA Copy Number Variations, Gene Dosage, Copy number analysis, Genome-wide association study, Bioinformatics, Malignancy, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Aged, Proportional Hazards Models, Hematology, business.industry, Myeloid leukemia, Genomics, Middle Aged, Genes, p53, Prognosis, medicine.disease, Leukemia, Myeloid, Acute, Leukemia, Treatment Outcome, 030104 developmental biology, medicine.anatomical_structure, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Mutation, Cytarabine, Female, business, Genome-Wide Association Study, medicine.drug
Abstract: Recent advances in genomic technologies have revolutionized acute myeloid leukemia (AML) understanding by identifying potential novel actionable genomic alterations. Consequently, current risk stratification at diagnosis not only relies on cytogenetics, but also on the inclusion of several of these abnormalities. Despite this progress, AML remains a heterogeneous and complex malignancy with variable response to current therapy. Although copy-number alterations (CNAs) are accepted prognostic markers in cancers, large-scale genomic studies aiming at identifying specific prognostic CNA-based markers in AML are still lacking. Using 367 AML, we identified four recurrent CNA on chromosomes 11 and 21 that predicted outcome even after adjusting for standard prognostic risk factors and potentially delineated two new subclasses of AML with poor prognosis. ERG amplification, the most frequent CNA, was related to cytarabine resistance, a cornerstone drug of AML therapy. These findings were further validated in The Cancer Genome Atlas data. Our results demonstrate that specific CNA are of independent prognostic relevance, and provide new molecular information into the genomic basis of AML and cytarabine response. Finally, these CNA identified two potential novel risk groups of AML, which when confirmed prospectively, may improve the clinical risk stratification and potentially the AML outcome.
Published: 2016
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21. Deletion 6q drives T-cell leukemia progression by ribosome modulation

Author: Wouter Van Loocke, Hervé Dombret, Samuel Quentin, Claude Gazin, David Avran, Pieter Van Vlierberghe, François Sigaux, André Baruchel, Delphine Briot, Jean-Jacques Diaz, Stéphanie Gachet, Tom Taghon, Emmanuelle Clappier, Gerben Menschaert, Tiama El-Chaar, Jules P.P. Meijerink, Marika Pla, Eulàlia Genescà, Jessica G.C.A.M. Buijs-Gladdines, Isabelle André-Schmutz, Jean Soulier, Marc Delord, Frédéric Catez, Lucie Hernandez, Willem K. Smits, Godelieve Meunier, Gabriel Therizols, Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Université Paris Diderot - Paris 7 (UPD7), Hémopathies Myéloïdes : Cellules Souches, Modèles Pré-Cliniques et Recherche Translationnelle (UMR 1131), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Princess Máxima Center for Pediatric Oncology, Center for Medical Genetics [Ghent], Ghent University Hospital, Cancer Research Institute (CRIG), Universiteit Gent = Ghent University (UGENT), 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), Department of Clinical Chemistry, Microbiology and Immunology, Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Service d'Hémato-oncologie [CHU Saint-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Collège de France - Chaire Oncologie cellulaire et moléculaire, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Universiteit Gent = Ghent University [Belgium] (UGENT), Chaire Oncologie cellulaire et moléculaire, 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)-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), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS), Ghent University [Belgium] (UGENT), 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 Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: 0301 basic medicine, Leukemia, T-Cell, Transplantation, Heterologous, T-cell leukemia, Haploinsufficiency, Biology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Heterogeneous-Nuclear Ribonucleoproteins, Mice, 03 medical and health sciences, RNA interference, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Humans, Gene silencing, Small nucleolar RNA, Gene, ComputingMilieux_MISCELLANEOUS, Gene Expression Profiling, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell biology, Gene expression profiling, 030104 developmental biology, Oncology, Tumor progression, Disease Progression, Chromosomes, Human, Pair 6, RNA Interference, RNA, Long Noncoding, Chromosome Deletion, Ribosomes, TAL1
Abstract: Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14, SYNCRIP (encoding hnRNP-Q) and SNHG5 (that hosts snoRNAs), both involved in regulating RNA maturation and translation. Combined silencing of both genes, but not of either gene alone, accelerated leukemogeneis in a Tal1/Lmo1/Notch1-driven mouse model, demonstrating the tumor-suppressive nature of the two-gene region. Proteomic and translational profiling of cells in which we engineered a short 6q deletion by CRISPR/Cas9 genome editing indicated decreased ribosome and mitochondrial activities, suggesting that the resulting metabolic changes may regulate tumor progression. Indeed, xenograft experiments showed an increased leukemia-initiating cell activity of primary human leukemic cells upon coextinction of SYNCRIP and SNHG5. Our findings not only elucidate the nature of 6q deletion but also highlight the role of ribosomes and mitochondria in T-ALL tumor progression. Significance: The oncogenic role of 6q deletion in T-ALL has remained elusive since this chromosomal abnormality was first identified more than 40 years ago. We combined genomic analysis and functional models to show that the codeletion of two contiguous genes at 6q14 enhances malignancy through deregulation of a ribosome–mitochondria axis, suggesting the potential for therapeutic intervention. This article is highlighted in the In This Issue feature, p. 1494
Published: 2018
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22. A landscape of germ line mutations in a cohort of inherited bone marrow failure patients

Author: Lucie Hernandez, Samuel Quentin, Elodie Lainey, Thierry Leblanc, Nicolas Boissel, Etienne Lengliné, Jean-Hugues Dalle, Julien Masliah-Planchon, Gérard Michel, Lionel Adès, Régis Peffault de Latour, Louis De Jaegere, Yves Bertrand, André Baruchel, Guy Leverger, Marie Sebert, Naddia Vasquez, Emmanuelle Clappier, Marc Muller, Olivier Bluteau, Stéphane Blanche, Isabelle Pellier, Gérard Socié, Wendy Cuccuini, Carine Domenech, Mathilde Hunault, Nicolas Blin, Raphael Itzykson, Sébastien Maury, Pierre Fenaux, Bénédicte Bruno, Mélanie Da Costa, Anna Raimbault, Jean Soulier, Claudine Schmitt, Arnaud Petit, Flore Sicre de Fontbrune, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), 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), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Recherche clinique appliquée à l'hématologie (URP_3518), Département de Néphrologie et transplantation [Hôpital Saint Louis - APHP], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service d'Hématologie Biologique [Hôpital Robert Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Service d'hématologie pédiatrique [Robert-Debré - APHP], Institut Universitaire d'Hématologie [Hôpital Saint-Louis - APHP], Laboratoire d’Hématologie [CHU Henri-Mondor - APHP], CHU Henri Mondor, Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Génétique [CHRU Nancy], Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Département d'Hématologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Département d'Hématologie [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service d'Immunologie Hématologie et Oncologie pédiatriques [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix Marseille Université (AMU), Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Université Paris Cité (UPCité), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-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)-Université Paris Cité (UPCité), CHU Henri Mondor [Créteil], Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, MECOM, DNA Mutational Analysis, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biochemistry, Cohort Studies, 03 medical and health sciences, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Fanconi anemia, Internal medicine, hemic and lymphatic diseases, Exome Sequencing, medicine, Humans, Child, Bone Marrow Diseases, Germ-Line Mutation, Exome sequencing, Chromosome 7 (human), business.industry, Infant, Newborn, Bone marrow failure, High-Throughput Nucleotide Sequencing, Infant, Cell Biology, Hematology, medicine.disease, Pancytopenia, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Child, Preschool, Myelodysplastic Syndromes, Female, Bone marrow, business
Abstract: International audience; Bone marrow (BM) failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented ≥5% BM blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged ≤2 years and 36.9% were ≥18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germ line mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (GATA2, RUNX1), telomeropathies (TERC, TERT, RTEL1), ribosome disorders (SBDS, DNAJC21, RPL5), and DNA repair deficiency (LIG4). Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in inherited BMF (IBMF), such as SAMD9 and SAMD9L (N = 16 of the 86 patients, 18.6%), MECOM/EVI1 (N = 6, 7.0%), and ERCC6L2 (N = 7, 8.1%), each of which was associated with a distinct natural history; SAMD9 and SAMD9L patients often experienced transient aplasia and monosomy 7, whereas MECOM patients presented early-onset severe aplastic anemia, and ERCC6L2 patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly recognized disease entities. Using a high-throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling.
Published: 2018
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23. Granulomonocytic progenitors are key target cells of azacytidine in higher risk myelodysplastic syndromes and acute myeloid leukemia

Author: Emmanuelle Clappier, Ashfaq Ali, Raphael Itzykson, Aline Massé, Aline Renneville, Jean Soulier, Hervé Dombret, Reinaldo Dal Bello, John E. Pimanda, Justine Penneroux, Emmanuel Raffoux, Raouf Ben Abdelali, Pierre Fenaux, Lucie Hernandez, Lionel Adès, Claude Preudhomme, Alexandre Puissant, Ashwin Unnikrishnan, and Samuel Quentin
Subjects: 0301 basic medicine, Cancer Research, medicine.medical_specialty, Antimetabolites, Antineoplastic, Myeloid, Pilot Projects, 03 medical and health sciences, Internal medicine, medicine, Biomarkers, Tumor, Humans, Prospective Studies, Progenitor cell, Regulation of gene expression, Hematology, business.industry, Myelodysplastic syndromes, Multipotent Stem Cells, Myeloid leukemia, High-Throughput Nucleotide Sequencing, medicine.disease, Hematopoietic Stem Cells, Prognosis, Gene Expression Regulation, Neoplastic, Leukemia, Leukemia, Myeloid, Acute, 030104 developmental biology, medicine.anatomical_structure, Oncology, Myelodysplastic Syndromes, Cancer research, Azacitidine, business, Granulocytes
Published: 2017

24. BET inhibitors impair leukemic stem cell function only in defined oncogenic subgroups of acute myeloid leukaemias

Author: Thorsten Braun, C. Gardin, Alexandre Puissant, Lucie Hernandez, Stéphanie Gachet, Lionel Adès, Raphael Itzykson, Jean Soulier, Justine Pasanisi, Ashfaq Ali, Louise Roulin, Aline Massé, Antonio José Alberdi, Jeannig Berrou, Marie Passet, Justine Penneroux, Marc Delord, Hervé Dombret, Samuel Quentin, Emmanuel Raffoux, and Emmanuelle Clappier
Subjects: Cancer Research, NPM1, Spliceosome, Myeloid, Aneuploidy, Antineoplastic Agents, Mice, Transgenic, Biology, Core binding factor, Mice, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Tumor Cells, Cultured, medicine, Animals, Humans, neoplasms, Neoplasm Staging, Hematopoietic Stem Cell Transplantation, Proteins, Oncogenes, Hematology, medicine.disease, Xenograft Model Antitumor Assays, Chromatin, Bromodomain, Leukemia, Myeloid, Acute, Treatment Outcome, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Mutation, Neoplastic Stem Cells, Cancer research, Stem cell, Nucleophosmin, 030215 immunology
Abstract: Bromodomain and Extra-Terminal inhibitors (BETi) such as OTX015 are active in Acute Myeloid Leukaemias (AML). Their activity on Leukemic Stem Cells (LSCs) is less documented. We interrogated the anti-LSC activity of OTX015 in a niche-like long-term culture in 26 primary AML samples and validated our findings in vivo. OTX015 impaired LSCs in AMLs harbouring Core Binding Factor or KMT2A gene fusions, NPM1 or chromatin/spliceosome genes mutations, but not in those with aneuploidy/TP53 mutations. In four patients, we dissected the transcriptomic footprint of Bet inhibition on LSCs versus blasts. Our results can instruct future clinical trials of BETi in AML.
Published: 2019
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25. Clinical and Molecular Characteristics of DDX41-Mutated Patients in a Large Cohort of Sporadic MDS/AML

Author: Marie Passet, Raphael Itzykson, Pierre Fenaux, Marie Sebert, Nadia Vasquez, Flore Sicre de Fontbrune, Régis Peffault de Latour, Anna Raimbault, Lionel Ades, Samuel Quentin, Emmanuelle Clappier, Emmanuel Raffoux, Ramy Rahmé, and Jean Soulier
Subjects: Oncology, medicine.medical_specialty, Cytopenia, business.industry, medicine.medical_treatment, Immunology, Cytogenetics, Cancer, Cell Biology, Hematology, Hematopoietic stem cell transplantation, medicine.disease, Biochemistry, Chemotherapy regimen, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, hemic and lymphatic diseases, Internal medicine, medicine, Aplastic anemia, business, Allele frequency, 030215 immunology
Abstract: Background: MDS and AML are mostly found in elderly patients. However, even in this population there is increasing evidence of predisposing genetic conditions, which have been underdiagnosed so far. Identifying inherited predisposition to myeloid disorders can be crucial especially in the context of hematopoietic stem cell transplantation (HSCT). Germline mutations in the DEAD/H-box helicase gene DDX41 have been identified in families with multiple cases of MDS or AML but also in sporadic cases. We aimed to analyze the prevalence and clinical features of DDX41-related myeloid malignancies within an unselected cohort of pts diagnosed with MDS or AML (MDS/AML). Methods Between March 2017 and June 2018, mutation screening was performed in 842 consecutive pts with a diagnosis of MDS/AML in a single center at Hôpital Saint-Louis, Paris. DNA was obtained from bone marrow or peripheral blood. Targeted sequencing of all exons of a panel of 80 genes recurrently mutated in myeloid malignancies was performed using custom capture-based library preparation (Agilent SureSelect) and Illumina sequencing. Sanger sequencing was performed on selected pts' cultured skin fibroblasts to check for the putative germline origin of the variants. Results We identified a DDX41 gene variant in 36 unrelated pts (4% of 842). We focused on the 32 pts having at least one DDX41 variant with a variant allele frequency (VAF) ranging from 40 to 60% highly suggestive of a germline origin, which was subsequently confirmed in all available cases (N=7). Sixteen variants were classified as pathogenic or likely pathogenic based on major predicted changes in protein sequence while the 16 others were missense variants of unknown significance (VUS), which scored deleterious in most algorithms (Figure 1A). An additional, likely somatic DDX41 mutation (VAF < 40%) was present in 18 of 32 pts (56%). Overall, 22 pts could be unambiguously considered as having a DDX41-related malignancy based on the presence of a major disturbing mutation and/or a second DDX41 mutation, while 10 pts had a single VUS. Twenty-six variants were newly described, including a recurrent one, G173R found in 5 pts, all having a second DDX41 mutation. Median age of the 32 patients was 70 years (35-88). Only 4 pts (12%) had a familial history of hematologic disorders. According to revised WHO classification, 4 (12.5%) had MDS-MLD, 8 MDS-EB (25%), 12 AML (37.5%), 6 MDS/MPN (18.7%), one 5q syndrome and one aplastic anemia. Strikingly, 15/32 (47%) pts had a history of cytopenia several years before blastic evolution and the 5 pts with G173R presented with hypoplastic MDS or initially isolated cytopenias, suggesting a specific functional effect of this mutation. Karyotype was normal in 16 pts (44%), complex in one, 12 pts had an isolated abnormality, and three had cytogenetic failure. Additional driver mutations were identified in most (27/32,84%) pts (Figure 1B), but we noticed that they were less frequent and at lower VAF in pts having both germline and somatic DDX41 mutations as compared to pts with a single variant (median 1.5 vs 3 mutations, median VAF 7% vs 29.5%, p Seven low-risk MDS pts were untreated, 7 received ESA and 5 (71%) responded. Ten high-risk MDS/AML pts received a hypomethylating agent and 8 (80%) achieved hematological response. Nine AML pts received intensive chemotherapy, with a complete response rate of 100% (7/7, 2 ongoing) and 5 of them had HSCT, all of them being alive with tolerable toxicity. Five pts died, median OS was 87 months, and 2-y OS was 89%. No difference on OS was observed between single and double-DDX41 mutated pts. Conclusions: DDX41 germline variant carriers represent a significant part of MDS/AML pts, the vast majority presenting without familial history. The predicted change in protein and/or the presence of a second somatic mutation strongly support the causality of the germline variant in most pts. By contrast with previous reports, pts frequently presented a phase of cytopenia before overt malignancy. Finally, outcome regarding response to treatment and OS in this DDX41-mutated cohort appeared relatively favorable. Figure 1. Figure 1. Disclosures Peffault De Latour: Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Fenaux:Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.
Published: 2018
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26. Insertion of an extra copy of Xq22.2 into 1p36 results in functional duplication of the PLP1 gene in a girl with classical Pelizaeus-Merzbacher disease

Author: Elissavet Konstantelou, Julien Masliah-Planchon, Florence Renaldo, Odile Boespflug-Tanguy, Cécile Pagan, Anne-Claude Tabet, George Vartzelis, Christina Kotsogianni, Céline Dupont, Eleonore Eymard-Pierre, Aurélien Trimouille, Mathilde Gay-Bellile, Séverine Drunat, Imen Dorboz, Monique Elmaleh, Samuel Quentin, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), UF de Cytogénétique, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Paediatric Neurology, 'A. & P. Kyriakou' Children's Hospital Athens, Equipe de recherche sur les traitements individualisés des cancers (ERTICa), Université d'Auvergne - Clermont-Ferrand I (UdA), Cytogénétique Médicale, CHU Clermont-Ferrand-Université d'Auvergne - Clermont-Ferrand I (UdA)-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Service de neurologie pédiatrique et maladies métaboliques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Service d'imagerie pédiatrique, This work was supported by grants from ELA Foundation (2009-007I4AV2)and 'Les amis de Ianis' association (Ploudaniel, France)., and BMC, BMC
Subjects: Ataxia, Pelizaeus-Merzbacher Disease, [SDV]Life Sciences [q-bio], Biology, Bioinformatics, X-inactivation, X Chromosome Inactivation, Gene Duplication, Gene duplication, Genomic Segment, Genetics, medicine, Humans, Genetics(clinical), Cognitive decline, Myelin Proteolipid Protein, In Situ Hybridization, Fluorescence, Genetics (clinical), Pelizaeus–Merzbacher disease, Microarray Analysis, medicine.disease, Magnetic Resonance Imaging, Hypotonia, 3. Good health, [SDV] Life Sciences [q-bio], Mutagenesis, Insertional, Chromosomes, Human, Pair 1, Progressive spasticity, Female, medicine.symptom, Research Article
Abstract: International audience; AbstractBackgroundPelizaeus-Merzbacher disease (PMD) is an X-linked dysmyelinating disorder characterized by nystagmus, hypotonia, ataxia, progressive spasticity, and cognitive decline. PMD classically results from a duplication of a genomic segment encompassing the entire PLP1 gene. Since the PLP1 gene is located in Xq22, PMD affects mostly boys.Methods and resultsHere we report the case of a girl with typical PMD. Copy number analysis of the PLP1 locus revealed a duplication of the entire gene and FISH analysis showed that the extra copy of the PLP1 gene was actually inserted in chromosome 1p36. This insertion of an additional copy of PLP1 in an autosome led to a functional duplication irrespective of the X-inactivation pattern. Subsequent overexpression of PLP1 was the cause of the PMD phenotype observed in this girl. Further sequencing of the breakpoint junction revealed a microhomology and thus suggested a replication based mechanism (such as FoSTeS or MMBIR).ConclusionThis case emphasizes the susceptibility of the PLP1 locus to complex rearrangement likely driven by the Xq22 local genomic architecture. In addition, careful consideration should be given to girls with classical PMD clinical features since they usually experience complex PLP1 genomic alteration with a distinct risk of inheritance.
Published: 2015
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27. Identification of mutations in TMEM5 and ISPD as a cause of severe cobblestone lissencephaly

Author: Louise Devisme, Koryna Socha, Malika Chelbi, Maryse Bonnière, Alix Clemenson, Marie Gonzales, Steven Gazal, Férechté Encha-Razavi, Catherine Fallet-Bianco, Jean-Pierre Bernard, Dominique Carles, Sylvie Odent, Annie Laquerrière, Anne Bazin, Christine Bole-Feysot, Céline Bouchet-Séraphin, Tania Attié-Bitach, Fabien Guimiot, Laurence Loeuillet, Nathalie Seta, Samuel Quentin, Sandrine Vuillaumier-Barrot, Jacqueline Aziza, Bernard Grandchamp, Sophie Monnot, Philippe Loget, Unité UMR_S956, Pôle de Pathologie, Centre de Biologie Pathologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pathologie et biologie cellulaire, Université de Montréal (UdeM)-Hôpital Sainte-Justine, Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de foetopathologie, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], LInguistique et DIdactique des Langues Étrangères et Maternelles (LIDILEM), Université Stendhal - Grenoble 3, Service de Biologie du Développement, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service d'Anatomie et de Cytologie Pathologiques, CHI Poissy-Saint-Germain, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Service de Cytogénétique et Embryologie, Laboratoire de biochimie métabolique et cellulaire, Hôpital Bichat - Claude Bernard, Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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 de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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), CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux ( Inserm U745 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'Anatomie et Cytologie Pathologique [Rouen], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement ( Néovasc ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institute for Research and Innovation in Biomedicine ( IRIB ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Sainte-Justine-Université de Montréal, Service d'anatomie et cytologie pathologiques [Rennes], Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), LInguistique et DIdactique des Langues Étrangères et Maternelles ( LIDILEM ), Université Stendhal - Grenoble 3-Université Grenoble Alpes ( UGA ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Service de Génétique et d'Embryologie Médicales, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -CHU Trousseau [APHP], Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université Stendhal - Grenoble 3-Université Grenoble Alpes (UGA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Trousseau [APHP], and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Genotype, Cobblestone Lissencephaly, [SDV]Life Sciences [q-bio], Lissencephaly, Gonadal dysgenesis, Consanguinity, Biology, medicine.disease_cause, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Fetus, Report, Gene Order, medicine, Dystroglycan, Genetics, Humans, Family, Genetics(clinical), Pentosyltransferases, Genetics (clinical), Alleles, 030304 developmental biology, 0303 health sciences, Mutation, [ SDV ] Life Sciences [q-bio], Membrane Proteins, Exons, Cortical dysplasia, medicine.disease, Nucleotidyltransferases, Introns, 3. Good health, biology.protein, 030217 neurology & neurosurgery
Abstract: International audience; Cobblestone lissencephaly is a peculiar brain malformation with characteristic radiological anomalies. It is defined as cortical dysplasia that results when neuroglial overmigration into the arachnoid space forms an extracortical layer that produces agyria and/or a "cobblestone" brain surface and ventricular enlargement. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal-recessive diseases characterized by cerebral, ocular, and muscular deficits. These include Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN, and FKRP identified these diseases as alpha-dystroglycanopathies. Our exhaustive screening of these six genes, in a cohort of 90 fetal cases, led to the identification of a mutation in only 53% of the families, suggesting that other genes might also be involved. We therefore decided to perform a genome-wide study in two multiplex families. This allowed us to identify two additional genes: TMEM5 and ISPD. Because TMEM has a glycosyltransferase domain and ISPD has an isoprenoid synthase domain characteristic of nucleotide diP-sugar transferases, these two proteins are thought to be involved in the glycosylation of dystroglycan. Further screening of 40 families with cobblestone lissencephaly identified nonsense and frameshift mutations in another four unrelated cases for each gene, increasing the mutational rate to 64% in our cohort. All these cases displayed a severe phenotype of cobblestone lissencephaly A. TMEM5 mutations were frequently associated with gonadal dysgenesis and neural tube defects, and ISPD mutations were frequently associated with brain vascular anomalies.
Published: 2012
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28. Cullin7: a new gene involved in liver carcinogenesis related to metabolic syndrome

Author: Miguel Albuquerque, Mouniya Mebarki, Stéphane Zalinski, Jean Soulier, Samuel Quentin, Pierre Bedossa, Valérie Paradis, Jacques Belghiti, and Lucie Hernandez
Subjects: Liver Cirrhosis, Male, Pathology, medicine.medical_specialty, Cirrhosis, Carcinoma, Hepatocellular, Hepatitis C virus, Blotting, Western, Gene Expression, Apoptosis, Biology, medicine.disease_cause, Real-Time Polymerase Chain Reaction, Cyclin D1, Downregulation and upregulation, medicine, Humans, neoplasms, Aged, Cell Proliferation, Aged, 80 and over, Chromosome Aberrations, Metabolic Syndrome, Cell growth, Liver Neoplasms, Gastroenterology, Nucleic Acid Hybridization, Transfection, Middle Aged, medicine.disease, Cullin Proteins, Hepatitis C, Immunohistochemistry, digestive system diseases, Cell Transformation, Neoplastic, Hepatocellular carcinoma, Cancer research, Chromosomes, Human, Pair 6, Female
Abstract: Metabolic syndrome (MS) is an emerging risk factor in hepatocellular carcinoma (HCC). HCC related to MS may occur either in advanced fibrosis or before the development of cirrhosis, suggesting involvement of different molecular pathways according to the features of background liver.To investigate genomic aberrations in HCC related to MS in order to identify new target genes involved in liver carcinogenesis.Chromosomal aberrations of HCC obtained from 20 patients with MS (HCC/MS) were studied by comparative genomic hybridisation and compared with HCC related to hepatitis C virus (HCV) infection (HCC/HCV, n=10) and, within the group of HCC with MS, according to the condition of the background liver (presence or absence of significant fibrosis).Among the most frequent chromosomal alterations observed in HCC, 6p21.1 amplification had a higher incidence in HCC/MS than in HCC/HCV (60% vs 20%, p0.01). Advanced fibrosis/cirrhosis in the peritumoral liver was the only clinicopathological factor associated with the 6p21.1 amplicon in HCC/MS. Increased expression of cullin7 (CUL7), a gene located at the 6p21.1 locus, was demonstrated in HCC with the 6p21.1 amplicon, in parallel with a decrease in cyclin D1 expression. CUL7 downregulation using siRNA transfection in hepatoma cell lines induced significant cyclin D1 expression (by promoting its degradation), decreased cell proliferation and increased apoptosis.This study demonstrates specific genomic alterations in HCC/MS and points to CUL7 as a novel gene potentially involved in liver carcinogenesis associated with MS, the amplification of which might influence cell proliferation.
Published: 2012

29. Meningioma progression in mice triggered by Nf2 and Cdkn2ab inactivation

Author: Michiko Niwa-Kawakita, Samuel Quentin, N El-Taraya, Anat Stemmer-Rachamimov, N Karboul, Marco Giovannini, Estelle Clermont-Taranchon, Matthieu Peyre, Michel Kalamarides, A Volk, and C Walczak
Subjects: Senescence, Cancer Research, Genotype, Vascular permeability, Biology, Meningioma, Mice, Chromosome instability, otorhinolaryngologic diseases, Genetics, medicine, Meningeal Neoplasms, Tumor Cells, Cultured, Animals, Gene Silencing, neoplasms, Molecular Biology, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p15, Chromosome Aberrations, Mice, Knockout, Neurofibromin 2, Gene Expression Profiling, Optical Imaging, Chromosome, medicine.disease, Magnetic Resonance Imaging, nervous system diseases, Gene Expression Regulation, Neoplastic, Disease Models, Animal, Phenotype, Animals, Newborn, Cell culture, Genetic Loci, Cancer research, Disease Progression, Syngenic, Neoplasm Grading, Comparative genomic hybridization
Abstract: Aggressive variants of meningiomas (WHO grade II and III) represent up to 30% of those tumors that are among the most common primary central nervous system tumors in adults. Currently, there is no effective treatment for grade-II and -III meningiomas, the main treatment remaining surgical excision. Genetic studies have highlighted two main events associated with meningioma progression: an increase of chromosomal instability in tumors with NF2 inactivation and homozygous deletions or point mutations of the CDKN2AB locus. In this study we demonstrated that in mice, in addition to bi-allelic Nf2 inactivation, homozygous and heterozygous Adenovirus Cre-mediated Cdkn2ab deletions lead to increased meningioma frequency (72% and 50%, respectively) with a shorter latency (3.5 and 7.8 months, respectively) compared with control cohorts and induce grade II/III meningioma progression with an incidence of 34% and 28%, respectively. Moreover, Cdkn2ab inactivation in arachnoidal cells was associated with decreased senescence compared with Nf2(-/-) and wild-type arachnoidal cells in vitro. We have established three mouse meningioma cell lines and generated a syngenic orthotopic meningioma mouse model with 50-100% grade-II/III meningiomas after reimplantation. Comparative genomic hybridization of four meningiomas from Cdkn2ab homozygous mice and three cell cultures revealed the absence of unbalanced chromosomal segments in tumors and several chromosome imbalances in cell cultures. In addition, we were able to detect meningiomas by using bioluminescence and to evaluate tumor vascular permeability by dynamic magnetic resonance imaging. These results show that Nf2 and Cdkn2ab cooperate to promote meningioma progression in mice. The short latency of tumor development and the ability to derive grade II/III meningioma cell cultures are key aspects of this model to promote its use in pre-clinical drug testing.
Published: 2012

30. Genomic imbalances detected by array-CGH in patients with syndromal ocular developmental anomalies

Author: Anne-Claude Tabet, Marion Gérard-Blanluet, Brigitte Benzacken, Jacques Elion, Nicolas Chassaing, Eva Pipiras, Serge Amselem, Pierre Bitoun, Céline Dupont, Sandrine Passemard, Annick Toutain, Alain Verloes, Samuel Quentin, Marie Legendre, Laurence Faivre, Andrée Delahaye, Frédérique Gatelais, Sophie Kaltenbach, Séverine Drunat, Pierre Gressens, Azzedine Aboura, Couvet, Sandrine, Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP. Nord - Université Paris Cité, Université Paris Cité (UPCité), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Faculté de Médecine Paris-Diderot [Paris], Université Paris Diderot - Paris 7 (UPD7), CHU d'Angers [Département Urgences], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hopital Saint-Louis [AP-HP] (AP-HP), Pharmacogénétique et abords thérapeutiques des maladies héréditaires, and Université des Antilles et de la Guyane (UAG)-Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, Adolescent, ocular developmental anomaly, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Genetic counseling, [SDV]Life Sciences [q-bio], Gene Dosage, 16p11.2 deletion, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Bioinformatics, Gene dosage, Genome, Article, Genetics, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, YWHAE, Copy-number variation, Eye Abnormalities, Child, Gene, Genetics (clinical), Chromosome Aberrations, Comparative Genomic Hybridization, Otx Transcription Factors, Microarray analysis techniques, Genome, Human, Forkhead Transcription Factors, Syndrome, [SDV] Life Sciences [q-bio], [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, array-CGH, Human genome, FOXC1, Female, Comparative genomic hybridization, OTX2
Abstract: International audience; In 65 patients, who had unexplained ocular developmental anomalies (ODAs) with at least one other birth defect and/or intellectual disability, we performed oligonucleotide comparative genome hybridisation-based microarray analysis (array-CGH; 105A or 180K, Agilent Technologies). In four patients, array-CGH identified clinically relevant deletions encompassing a gene known to be involved in ocular development (FOXC1 or OTX2). In four other patients, we found three pathogenic deletions not classically associated with abnormal ocular morphogenesis, namely, del(17)(p13.3p13.3), del(10)(p14p15.3), and del(16)(p11.2p11.2). We also detected copy number variations of uncertain pathogenicity in two other patients. Rearranged segments ranged in size from 0.04 to 5.68 Mb. These results show that array-CGH provides a high diagnostic yield (15%) in patients with syndromal ODAs and can identify previously unknown chromosomal regions associated with these conditions. In addition to their importance for diagnosis and genetic counselling, these data may help identify genes involved in ocular development.
Published: 2012
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31. First description of ABCB4 gene deletions in familial low phospholipid-associated cholelithiasis and oral contraceptives-induced cholestasis

Author: Philippe Ponsot, Ingrid Laurendeau, Béatrice Parfait, Eric Pasmant, Yann Consigny, Jian-Min Chen, Olivier Farges, Michel Vidaud, Samuel Quentin, Bertrand Condat, Dominique Vidaud, P Goussard, Laetitia Baranes, Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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 de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, medicine.medical_specialty, ATP Binding Cassette Transporter, Subfamily B, Cholestasis, Intrahepatic, Gallbladder Diseases, Gene dosage, Gastroenterology, Article, Biliary disease, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Cholestasis, Cholelithiasis, Internal medicine, Genotype, Genetics, Humans, Medicine, LPAC, Genotyping, Genetics (clinical), 030304 developmental biology, Comparative Genomic Hybridization, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Base Sequence, business.industry, Progressive familial intrahepatic cholestasis, Syndrome, ABCB4, Middle Aged, medicine.disease, Pedigree, 3. Good health, Pregnancy Complications, Female, 030211 gastroenterology & hepatology, business, Chromosomes, Human, Pair 7, Gene Deletion, Cholestasis of pregnancy, Contraceptives, Oral
Abstract: International audience; The wide clinical spectrum of the ABCB4 gene (ATP-binding cassette subfamily B member 4) deficiency syndromes in humans includes low phospholipid-associated cholelithiasis (LPAC), intrahepatic cholestasis of pregnancy (ICP), oral contraceptives-induced cholestasis (CIC) and progressive familial intrahepatic cholestasis type 3 (PFIC3). No ABCB4 mutations are found in a significant proportion of patients with these syndromes. In the present study, 102 unrelated adult patients with LPAC (43 patients) or CIC/ICP (59 patients) were screened for ABCB4 mutations using DNA sequencing. Heterozygous ABCB4 point or short insertion/deletion mutations were found in 37% (16/43) of LPAC patients and in 27% (16/59) of ICP/CIC patients. High resolution gene dosage methodologies were used in the 70 negative patients. Here, we describe for the first time ABCB4 partial or complete heterozygous deletions in 7% (3/43) of LPAC patients, and in 2% (1/59) of ICP/CIC patients. Our observations urge to systematically test patients with LPAC, ICP/CIC, and also children with PFIC3 for the presence of ABCB4 deletions using molecular tools allowing detection of gross rearrangements. In clinical practice, a comprehensive ABCB4 alteration screening algorithm will permit the use of ABCB4 genotyping to confirm the diagnosis of LPAC or ICP/CIC, and allow familial testing. An early diagnosis of these biliary diseases may be beneficial because of the preventive effect of ursodeoxycholic acid on biliary complications. Further comparative studies of patients with well-characterized genotypes (including deletions) and phenotypes will help determine whether ABCB4 mutation types influence clinical outcomes.
Published: 2011
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32. Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic RUNX1/AML1 lesions

Author: Claude Preudhomme, Nadia Vasquez, Eliane Gluckman, Corinne Pondarré, Mauricette Michallet, Jean-Hugues Dalle, Gérard Michel, Wendy Cuccuini, Vanderson Rocha, Samuel Quentin, Raphael Ceccaldi, Jérôme Larghero, Dominique Stoppa-Lyonnet, Jean Soulier, Olivier Nibourel, François Sigaux, Pascale Schneider, Gérard Socié, Régis Peffault de Latour, Thierry Leblanc, André Baruchel, Catherine Dubois d'Enghien, and Marie-Pierre Pages
Subjects: Adult, Male, Pathology, medicine.medical_specialty, NPM1, Adolescent, Immunology, Gene Dosage, Chromosomal translocation, Biology, Biochemistry, Somatic evolution in cancer, Polymorphism, Single Nucleotide, Genomic Instability, Loss of heterozygosity, Young Adult, Fanconi anemia, Bone Marrow, hemic and lymphatic diseases, medicine, Humans, Genes, Tumor Suppressor, Aplastic anemia, Child, Gene Expression Regulation, Leukemic, Gene Expression Profiling, Homozygote, Myeloid leukemia, Cell Biology, Hematology, Middle Aged, medicine.disease, Leukemia, Leukemia, Myeloid, Acute, Fanconi Anemia, Child, Preschool, Myelodysplastic Syndromes, Core Binding Factor Alpha 2 Subunit, Cancer research, Female, Nucleophosmin
Abstract: Fanconi anemia (FA) is a genetic condition associated with bone marrow (BM) failure, myelodysplasia (MDS), and acute myeloid leukemia (AML). We studied 57 FA patients with hypoplastic or aplastic anemia (n = 20), MDS (n = 18), AML (n = 11), or no BM abnormality (n = 8). BM samples were analyzed by karyotype, high-density DNA arrays with respect to paired fibroblasts, and by selected oncogene sequencing. A specific pattern of chromosomal abnormalities was found in MDS/AML, which included 1q+ (44.8%), 3q+ (41.4%), −7/7q (17.2%), and 11q− (13.8%). Moreover, cryptic RUNX1/AML1 lesions (translocations, deletions, or mutations) were observed for the first time in FA (20.7%). Rare mutations of NRAS, FLT3-ITD, MLL-PTD, ERG amplification, and ZFP36L2-PRDM16 translocation, but no TP53, TET2, CBL, NPM1, and CEBPα mutations were found. Frequent homozygosity regions were related not to somatic copy-neutral loss of heterozygosity but to consanguinity, suggesting that homologous recombination is not a common progression mechanism in FA. Importantly, the RUNX1 and other chromosomal/genomic lesions were found at the MDS/AML stages, except for 1q+, which was found at all stages. These data have implications for staging and therapeutic managing in FA patients, and also to analyze the mechanisms of clonal evolution and oncogenesis in a background of genomic instability and BM failure.
Published: 2011

33. Intragenic rearrangements in LARGE and POMGNT1 genes in severe dystroglycanopathies

Author: Férechté Encha-Razavi, A. Eude-Caye, C. Besson, Bernard Grandchamp, Odile Boute, C. Bouchet-Seraphin, M. Chelbi, Louise Devisme, Brigitte Gilbert-Dussardier, E. Charluteau, C. Le Bizec, Philippe Loget, Samuel Quentin, Alice Goldenberg, Nathalie Seta, Kim Maincent, Marie Gonzales, P. Landrieu, and Sandrine Vuillaumier-Barrot
Subjects: Male, DNA Mutational Analysis, Biology, medicine.disease_cause, N-Acetylglucosaminyltransferases, Exon, Consanguinity, Fetus, Gene Duplication, Gene duplication, medicine, Humans, Muscular dystrophy, Child, Gene, Genetics (clinical), Sequence Deletion, Genetics, Mutation, Sequence Analysis, RNA, Point mutation, Intron, Walker-Warburg Syndrome, Exons, medicine.disease, Phenotype, Neurology, Pediatrics, Perinatology and Child Health, Neurology (clinical), Microsatellite Repeats
Abstract: Dystroglycanopathies are a heterogeneous group of muscular dystrophies with autosomal recessive inheritance characterized by abnormal glycosylation of alpha-dystroglycan. The most severe phenotypes are Walker-Warburg Syndrome (WWS) and muscle-eye-brain disease (MEB) presenting with lissencephaly type II (LIS II) and in which muscular dystrophy is associated with mental retardation and eye abnormalities. To date, six distinct genes, POMT1 , POMT2 , POMGNT1 , FKTN , FKRP , LARGE and recently in one case DPM3 , have been shown to be involved in dystroglycanopathies. Genomic sequencing alone is still frequently used for diagnosis purpose, not allowing detection of intragenic rearrangements at the heterozygous state contrarily to RNA analysis, quantitative PCR and CGH array analysis. These latter methods enabled us to identify four new intragenic rearrangements in the LARGE gene in three fetuses with WWS, born to two unrelated families: deletion of exons 9–10 and duplication of introns 1–4 for the first family and deletion of exons 4 and 7 for the second one; and a deletion of the last six exons of the POMGNT1 gene in two unrelated MEB patients. Genomic dosage studies using emerging tools such as CGH array should be included in routine molecular analysis of dystroglycanopathies, not only for the screening of the LARGE gene in which this kind of mutation seems to be more frequent than point mutations, but also for the other involved genes, especially in severe clinical cases.
Published: 2011

34. Incidence and prognostic value of TET2 alterations in de novo acute myeloid leukemia achieving complete remission

Author: Aline Renneville, Nathalie Philippe, Olivier Kosmider, Christophe Roumier, Olivier Bernard, Hervé Dombret, Claude Preudhomme, Sandrine Geffroy, François Dreyfus, Pierre Fenaux, Michaela Fontenay, Jean-Michel Cayuela, Olivier Nibourel, Meyling Cheok, Bruno Quesnel, Samuel Quentin, Nicolas Boissel, Catherine Roche-Lestienne, William Vainchenker, and Jean Soulier
Subjects: Oncology, Adult, Male, medicine.medical_specialty, NPM1, Tumor suppressor gene, Adolescent, Immunology, Chromosomal translocation, Single-nucleotide polymorphism, Biology, Biochemistry, Polymorphism, Single Nucleotide, Translocation, Genetic, Dioxygenases, Young Adult, Internal medicine, Proto-Oncogene Proteins, medicine, Biomarkers, Tumor, Humans, Aged, Oligonucleotide Array Sequence Analysis, Hematology, Point mutation, Gene Expression Profiling, Incidence, Remission Induction, Myeloid leukemia, Cancer, Cell Biology, Middle Aged, medicine.disease, Prognosis, DNA-Binding Proteins, Survival Rate, Leukemia, Myeloid, Acute, Karyotyping, Mutation, Female, Nucleophosmin
Abstract: Mutations of the ten eleven translocation 2 gene (TET2) have recently been reported in myelodysplastic syndrome and myeloproliferative neoplasms. We analyzed the incidence and prognostic value of TET2 point mutations and other genomic alterations by direct sequencing and single nucleotide polymorphism microarray analysis in 111 de novo acute myeloid leukemia, who had all achieved complete remission (CR). Mutations were observed in 19 (17%) of the 111 patients compared with 10 (27%) of 36 patients who had failed to achieve CR (P = .2). In the 111 patients who had achieved CR, TET2 alterations were only significantly associated with NPM1 mutations but not with other pretreatment characteristics. TET2 gene status was not significantly correlated with disease-free survival and overall survival, both in the entire cohort and in patients with normal karyotype.
Published: 2010

35. Impact of increasing NaCl concentrations on the performance and community composition of two anaerobic reactors

Author: Olivier Lefebvre, Jean-Jacques Godon, J.P. Delgenes, Samuel Quentin, René Moletta, Michel Torrijos, Laboratoire de Biotechnologie de l'Environnement [Narbonne] (LBE), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA)
Subjects: Molecular Sequence Data, 0211 other engineering and technologies, Vinasse, Wine, 02 engineering and technology, 010501 environmental sciences, Biology, Euryarchaeota, Sodium Chloride, 01 natural sciences, 7. Clean energy, Applied Microbiology and Biotechnology, DNA, Ribosomal, Polymerase Chain Reaction, Microbiology, Bacteria, Anaerobic, Bioreactors, RNA, Ribosomal, 16S, Food science, Anaerobiosis, Effluent, Ecosystem, Polymorphism, Single-Stranded Conformational, 0105 earth and related environmental sciences, 021110 strategic, defence & security studies, Ethanol, Sewage, MICROBIAL COMMUNITY, HALOTOLERANCE, 16S RIBOSOMAL RNA, General Medicine, Sequence Analysis, DNA, 6. Clean water, Halophile, Anaerobic digestion, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Microbial population biology, Wastewater, Halotolerance, ANAEROBIC SBR, Anaerobic exercise, Biotechnology
Abstract: The anaerobic treatment of saline effluents using halophilic and halotolerant microbial consortia is of major interest. Inhibition of anaerobic digestion is known to occur at high salt content. However, it seems that the suitable adaptation of an anaerobic sludge makes possible the treatment of saline wastewater. In this study, a non-saline anaerobic sludge was inoculated in two anaerobic batch reactors operating with a different substrate (distillery vinasse and ethanol) and subjected to increasing NaCl concentrations. The performance of the digesters appeared to be highly dependent on the nature of the substrate, and a similar level of inhibition (i.e. around 90% of the specific loading rate and specific methanogenic activity) was stated at 10 g l(-1) of NaCl with distillery vinasse and 60 g l(-1) of NaCl with ethanol. The characterization of the microflora and its adaptation to increasing NaCl conditions were also investigated using molecular tools based on the analysis of genomic 16S rDNA. The microbial communities revealed a high diversity that could be maintained in both reactors despite the increase in NaCl concentrations.
Published: 2006
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36. SNP Array Analysis in Acute Myeloid Leukemia Reveals Frequent and Recurrent Acquired Genetic Alterations Linked to Prognosis: a Study of the ALFA Group

Author: Antonio José Alberdi, Claude Preudhomme, Céline Berthon, Sandrine Geffroy, Martin Figeac, Céline Villenet, Olivier Nibourel, Christophe Roumier, Jean Soulier, Samuel Quentin, Aline Renneville, Meyling Cheok, and Hervé Dombret
Subjects: Candidate gene, medicine.medical_specialty, Immunology, Cytogenetics, Single-nucleotide polymorphism, Cell Biology, Hematology, Biology, Bioinformatics, medicine.disease, Biochemistry, Uniparental disomy, Transplantation, CEBPA, medicine, Copy-number variation, SNP array
Abstract: Abstract 2533 Acute myeloid leukemia (AML) is a heterogeneous disease because of different leukemogenic mechanisms and variable response to antileukemic treatment. In addition to age and leukocytosis at diagnosis, cytogenetic abnormalities are key factors to assess prognosis. Several gene alterations such as those involving CEBPa, NPM1 and FTL3 have been identified and have improved the classification of AML. However, variability remains and cannot be completely explained. In this study, we performed SNP array analysis on a cohort of 128 AML patients in order to identify new genetic alterations and potential new candidate genes involved in leukemogenesis or disease progression. Patients were classified according to MRC cytogenetics (26 favourable; 77 intermediates, 15 adverse, 10 no informative caryotype). Patients were aged from 11 to 65 years and distributed across all French-American-British (FAB) classes except M3 (8 M0, 25 M1, 38 M2, 26 M4 and 11 M4Eo, 12 M5, 2 M6), Paired DNA was extracted from bone marrow aspirates obtained at diagnosis and after achieving complete remission (CR), and analyzed using Affymetrix Genome-Wide Human SNP Array 6.0 to distinguish acquired from constitutional genetic abnormalities. Copy number variations (CNA) were validated on a custom Agilent microarray (Human Genome CGH Microarray 105k). Data were analyzed using Affymetrix' Genotyping Console 3.0.2, Agilent's GeneSpring GX. Statistical analyses were executed using R version 12.1. The Cox proportional hazard regression model was used to relate genetic abnormalities to treatment outcome, with karyotype included as the second covariate. Time was censored at transplantation date if bone marrow transplantation was performed. We found 210 genomic abnormalities in 74 patients: 197 CNA and 13 copy neutral losses of heterozygosity (uniparental disomy or UPD), resulting in 1.6 abnormalities on average per patient (range 0 to 17). Among CNA, deletions were more frequent than gains (130 vs. 66). CNA spanned from 8kb to 191MB (median of gains 24MB, median of losses 2MB). 116 of them had not been detected by conventional cytogenetics. UPD spanned from 23MB to 150MB (median, 33 MB). Abnormalities were located over all chromosomes except for chromosome14 and were particularly frequent on chromosomes 2, 7, 11, 16, 17, and 21 (54% of all abnormalities). We defined 72 minimal common regions which were altered in at least 2 patients. Among the 43 common regions shorter than 5Mb, 16 contain at least one gene reported in AML or cancer. CNA and UPD were distributed across all FAB subtypes. Of note, 7 of 8 patients with AML M0 had 1 or more abnormalities. Among the 74 patients with CNA or UPD, 36 had an intermediate caryotype. We found no significant association of number of abnormalities with known gene alterations known to influence prognosis (i.e., CEBPa, FLT3itd or NPM). As expected, there were significantly more alterations in patients with a favourable or adverse caryotype (P=0.0045, Fisher's exact test). Furthermore, the number of genetic abnormalities was significantly associated to disease-free and to overall survival (P=0.010 and 0.0016, respectively). This remained significant in a multivariate analysis including karyotype (P=0.046 and 0.01, respectively) CNA or UPD was detected in 56% of AML patients who achieved remission of these 45% have intermediate cytogenetics. We identified 43 minimal common regions shorter than 5MB, which were altered in at least 2 patients and 37% of these regions involve genes previously reported in AML or cancer. Increased genomic alterations were significantly associated with favorable and adverse cytogenetics and with disease-free and overall survival. Prognostic significance of number of abnormalities remains significant after adjustment for cytogenetics. DNA SNP array analysis may be useful to better define prognostic subgroups in addition to conventional cytogenetics and may identify candidate genes implicated in leukemogenesis or disease progression. Disclosures: No relevant conflicts of interest to declare.
Published: 2011
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37. Coopération de NF2 et CDKN2AB dans un modèle murin transgénique de méningiome de grade 2/3

Author: M. Niwa-Kawakita, Marco Giovannini, Michel Kalamarides, E. Taranchon, A O Stemmer-Rachamimov, Matthieu Peyre, and Samuel Quentin
Subjects: Surgery, Neurology (clinical)
Published: 2011
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38. 260 Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes RUNX1/AML1 lesions

Author: Eliane Gluckman, V. Rocha, Gérard Socié, Wendy Cuccuini, Samuel Quentin, Mauricette Michallet, Corinne Pondarré, André Baruchel, Olivier Nibourel, Raphael Ceccaldi, Dominique Stoppa-Lyonnet, R. Peffault de Latour, Marie-Pierre Pages, Claude Preudhomme, François Sigaux, Pascale Schneider, Jean Soulier, Thierry Leblanc, and G. Michel
Subjects: Cancer Research, Leukemia, Oncology, Fanconi anemia, business.industry, medicine, Cancer research, Runx1 aml1, Hematology, medicine.disease, business
Published: 2011
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39. Association of TET2 Alterations with NPM1 Mutations and Prognostic Value in De Novo Acute Myeloid Leukemia (AML)

Author: Jean Soulier, William Vainchenker, Nicolas Boissel, Christophe Roumier, Pierre Fenaux, Francois Dreyfus, Jean-Michel Cayuela, Bruno Quesnel, Aline Renneville, Claude Preudhomme, Olivier Bernard, Catherine Roche-Lestienne, Nathalie Philippe, Meyling Cheok, Sandrine Geffroy, Hervé Dombret, Michaela Fontenay, Olivier Kosmider, Olivier Nibourel, and Samuel Quentin
Subjects: Oncology, Mutation, Pathology, medicine.medical_specialty, Point mutation, Immunology, Single-nucleotide polymorphism, Cell Biology, Hematology, Biology, medicine.disease_cause, Biochemistry, Frameshift mutation, Internal medicine, Genotype, CEBPA, medicine, Missense mutation, SNP array
Abstract: Abstract 163 In acute myeloid leukemia (AML), both cytogenetic and molecular abnormalities are strongly associated with prognosis. In particular, in cytogenetically normal AML (CN-AML), FLT3-ITD (internal tandem duplication) carries adverse prognostic factor whereas NPM1 or CEBPA mutations are associated with favorable outcome. Recently, mutations of the ten eleven translocation 2 gene (TET2) have been reported myeloid neoplasms. We evaluated the frequency and prognostic value of TET2 alterations, in a cohort of 111 de novo AML patients. We studied 111 patients aged between 15 years and 69 years with previously untreated de novo AML who had reached complete remission (CR) using intensive chemotherapy. 28 of them also received an allogenic bone marrow transplantation in first CR. Analysis of TET2 sequence variation was performed by direct sequencing of PCR products from 111 genomic DNA samples obtained at diagnosis. Frameshift and nonsense variations were all scored as mutation whereas missense mutations were retained when observed at diagnostic but absent in the CR paired sample obtained. Previously identified single nucleotide polymorphisms (SNP) were not considered. TET2 anomalies were numbered according to Genebank reference FM992369. Paired diagnosis and CR genomic DNAs were analyzed using Affymetrix Genome-Wide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA). Data were analyzed using Gene Chip Genotyping Console 3.0.2 and Partek Genomics Suite (www.partek.com/). Comparisons were made by Fisher's exact test for binary variables and the Mann-Whitney‘s test for continuous variables. Disease Free Survival (DFS) and overall survival (OS) were calculated according to the Kaplan-Meier method. Comparisons regarding DFS and OS were performed with the log-rank test. 24 acquired TET2 mutations were observed in 19 of the 111 (17%) de novo AML patients, suggesting the alteration of the two TET2 alleles in 5 patients. They included 21 different events: 6 frameshift, 7 non-sense and 11 missense mutations. Four of the missense mutations were located in conserved regions and 7 outside. All of them were detected in the diagnostic sample but were absent in the paired remission sample. Except for two missense mutations (S282F, T492S) both detected in two patients, no recurrent TET2 mutation was observed. Acquired mutations were spread over all exons. No case of uniparental disomy (UPD) was observed and only one patient presented a small deletion of 60Kb in the TET2 gene locus without TET2 mutation. No significant difference was observed between patients with or without TET2 alterations for gender, age, hemoglobin level, platelet count, FAB subtypes distribution and cytogenetics according to MRC classification, but there was a trend for higher WBC count in patients with TET2 alteration. No significant association was observed between TET2 mutations and FLT3 or CEBPA alterations. However, TET2 alterations were significantly associated with NPM1 mutations (p=0.032). In the entire patient cohort, no difference in DFS or OS was seen between patients with and without TET2 alteration. However, a significantly worse DFS was observed for patients presenting TET2 mutations within the subgroup of patients with NPM1 mutations (3y-DFS: 0% vs 66.4%, 95% CI [45.6–87.2], p=0.008) Considering both the favorable prognosis of NPM1 mutations without FLT3-ITD in CN-AML and the absence of clear association between FLT3-ITD and TET2 alterations in this study, prognostic value of the genotype characterized by NPM1 mutation without FLT3-ITD or TET2 alteration (NPM1+FLT3-ITD-TET2-) was compared to other patients within CN-AML group (N=54). NPM1+FLT3-ITD-TET2- patients showed a significantly better DFS and OS compared to other patients in CN-AML group (3y-DFS: 82.1%, 95% CI [59.1–100] vs 37.3%, 95% CI [20.2–54.3], p=0.01; 3y-OS: 80.8%, 95% CI [56.1–100] vs 42.3%, 95% CI [23.3–61.3], p=0.04). In conclusion, we observed point mutations of TET2 in 17% of patients, whereas TET2 deletion or UPD are very rare. In our study, TET2 mutations were clearly associated with NPM1 mutations and carried a negative prognostic impact in this subgroup. Screening for TET2 mutations may improve the characterization of CN-AML and help to identify within the low-risk subgroup with NPM1 mutation and without FLT3-ITD, patients at high risk of relapse. Disclosures: Fenaux: Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

40. A Recurrent Pattern of Acquired Genomic Abnormalities In Myelodysplasia and Leukemia of Fanconi Anemia Includes Cryptic RUNX1/AML1 abnormalities

Author: André Baruchel, Samuel Quentin, Catherine Dubois d'Enghien, Raphael Ceccaldi, Dominique Stoppa-Lyonnet, Olivier Nibourel, Vanderson Rocha, Claude Preudhomme, Mauricette Michallet, Régis Peffault de Latour, Eliane Gluckman, Jean-Pierre Vannier, Corinne Pondarré, Jean Soulier, Nadia Vasquez, Gérard Michel, Gérard Socié, Thierry Leblanc, Wendy Cuccuini, Jérôme Larghero, and Marie-Pierre Pages
Subjects: NPM1, Pathology, medicine.medical_specialty, medicine.medical_treatment, Immunology, Bone marrow failure, Cell Biology, Hematology, Hematopoietic stem cell transplantation, Biology, medicine.disease, Biochemistry, Leukemia, medicine.anatomical_structure, Fanconi anemia, hemic and lymphatic diseases, CEBPA, medicine, Bone marrow, Aplastic anemia
Abstract: Abstract 975 Fanconi anemia (FA) is a rare genetic condition characterized by congenital abnormalities, chromosome fragility, progressive bone marrow failure during childhood, and cancer susceptibility. FA patients experience a high risk to develop myelodysplasia (MDS) and secondary-type acute myeloid leukemia (AML) during their teens or in young adulthood. Severity of the cytopenia, excess of blast cells and presence of a cytogenetic clone in the bone marrow are usual criteria to undertake hematopoietic stem cell transplantation. In order to investigate the pattern of chromosomal and genomic abnormalities during bone marrow progression in FA and their association to MDS/AML, we analyzed bone marrow samples from FA patients using a wide panel of chromosomal and molecular techniques including DNA microarrays and oncogene sequencing. This series of FA patients was enriched in patients older than 18 year-old and/or with morphological or karyotypic abnormalities on the follow up BM aspirate. 57 FA patients were included, aged 4 to 57 yo (median 18); FA groups were FA-A (n=49), FA-G (n=1), FA-D2 (n=1), FA-D1 (n=1) and undertermined (n=5). Bone marrow morphology was hypoplastic/aplastic anemia (n=20), MDS (n=18, mainly RCMD and RAEB according to the WHO 2008 classification), AML (n=11), or no abnormality except the usual mild dyserythropoiesis of FA (n=8). Bone marrow samples were analyzed by karyotype, FISH, high density array-CGH and/or SNP-arrays with respect to the paired fibroblast DNAs, and by sequencing of selected oncogenes and tumor suppressor genes. A specific pattern of genomic abnormalities due to unbalanced translocations was found in the 29 MDS/AML, which included 1q+ (44.8%), 3q+ (41.3%), -7/7q (17.2%), and 11q- (13.8%). Moreover, cryptic abnormalities (translocations, deletions or mutations) of the RUNX1/AML1 gene were evidenced for the first time in FA, in 6 out of the 29 patients with MDS or AML (20.7%). By contrast, mutations of FLT3-ITD, MLL-ITD, and N-RAS, but not TP53, CBL, TET2, CEBPa, NPM1, and FLT3-TKD, were rarely found. Frequent homozygosity regions were evidenced by SNP-array in 11 patients, but the analysis of the paired fibroblast DNA and the constitutional FANC mutations demonstrated that they were not related to somatic copy-neutral loss of heterozygosity but to consanguinity. Importantly, the RUNX1/AML1 and other chromosomal/genomic abnormalities were found at the MDS and AML stages only, except for 1q+ which could be found at any stages including normal bone marrow morphology. In our experience 1q+ does not predict systematically a transformation into MDS/AML in the following years. These data have important implications, not only for the cytogenetic staging of the bone marrow cells in FA patients with an impact for therapeutic managing, but also as a basis to investigate the multistep clonal selection and related oncogenesis in patients with hypoplastic bone marrow and genomic instability, with potential relevance for non-FA patients. Disclosures: Gluckman: Cord-use: Membership on an entity's Board of Directors or advisory committees.

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