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3 results on '"Godelieve, Meunier"'

1. 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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2. First-line therapy for chronic lymphocytic leukemia in patients older than 79 years is feasible and achieves good results: A FILO retrospective study

Author

Godelieve, Meunier, Loic, Ysebaert, Phi Linh, Nguyen-Thi, Stéphane, Lepretre, Anne, Quinquenel, Jehan, Dupuis, Richard, Lemal, Thérèse, Aurran, Cécile, Tomowiak, Florence, Cymbalista, Marie Sarah, Dilhuydy, Annie, Brion, Pierre, Morel, Bruno, Cazin, Véronique, Leblond, Guillaume, Cartron, Daniel, Ré, Marie Christine, Béné, Anne Sophie, Michallet, and Pierre, Feugier

Subjects
Aged, 80 and over, Chromosome Aberrations, Male, Age Factors, Prognosis, Leukemia, Lymphocytic, Chronic, B-Cell, Survival Analysis, Treatment Outcome, Socioeconomic Factors, Antineoplastic Combined Chemotherapy Protocols, Mutation, Humans, Female, Biomarkers, Neoplasm Staging, Retrospective Studies
Abstract

The mean age at diagnosis of chronic lymphocytic leukemia (CLL) is 72 years, with 22.8% of patients being older than 80 years. However, the elderly are underrepresented in clinical studies of CLL. We performed a retrospective study of CLL patients aged 80 years or older at the initiation of first-line therapy in hospitals affiliated with the French intergroup on CLL (French Innovative Leukemia Organization) between 2003 and 2013. Here, we describe the clinical and biological characteristics, treatment, and outcomes for 201 patients. The median age of the cohort was 83.2 years (80-92 years). The median Cumulative Index Rating Scale comorbidity score was 5 and the median creatinine clearance was 48 mL/min (Cockcroft-Gault formula). At treatment initiation, Binet stage was A (26.4%), B (27.9%), or C (40.3%). Therapy consisted mainly of chlorambucil (65.7%), bendamustine (10.5%), and rituximab (44.3%) as follows: chlorambucil alone (45.3%) or immunochemotherapy (48.3%) with rituximab + chlorambucil (22.7%), rituximab + bendamustine (10.4%), or rituximab + cyclophosphamide + dexamethasone (5.5%). The overall response rate was 66.2% with 31.8% clinical complete remission. The median overall and progression-free survival from treatment initiation was 53.7 and 18.3 months, respectively. These results suggest that treatment is feasible in this age group, even with immunochemotherapy. Thus, prospective trials should target this population and oncogeriatric evaluation and new targeted therapies should be part of such future trials.

Published
2016

3. Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition

Author

Lise Willems, Nathalie Jacque, Anne Marie Ronchetti, Catherine Lacombe, Susan Demo, Clément Larrue, Jerome Tamburini, Laury Poulain, Christian Recher, Nicolas Chapuis, Rudy Birsen, Godelieve Meunier, Didier Bouscary, Patrick Mayeux, Laure Joseph, Estelle Saland, Mireille Lambert, Jean-Emmanuel Sarry, Ivan C. Moura, Justine Decroocq, Thiago Trovati Maciel, and Pierre Sujobert

Subjects
Glutamine, Immunology, Citric Acid Cycle, Benzeneacetamides, Antineoplastic Agents, Apoptosis, Biology, Biochemistry, Oxidative Phosphorylation, Mice, Oxygen Consumption, Glutaminase, Cell Line, Tumor, Thiadiazoles, medicine, Animals, Humans, Enzyme Inhibitors, Cell Proliferation, Gene knockdown, Sulfonamides, Glutaminolysis, Cell growth, Myeloid leukemia, Cell Biology, Hematology, medicine.disease, Bridged Bicyclo Compounds, Heterocyclic, Molecular biology, Xenograft Model Antitumor Assays, Mitochondria, Leukemia, Leukemia, Myeloid, Acute, Proto-Oncogene Proteins c-bcl-2, Gene Knockdown Techniques, Cancer cell, Cancer research
Abstract

Cancer cells require glutamine to adapt to increased biosynthetic activity. The limiting step in intracellular glutamine catabolism involves its conversion to glutamate by glutaminase (GA). Different GA isoforms are encoded by the genes GLS1 and GLS2 in humans. Herein, we show that glutamine levels control mitochondrial oxidative phosphorylation (OXPHOS) in acute myeloid leukemia (AML) cells. Glutaminase C (GAC) is the GA isoform that is most abundantly expressed in AML. Both knockdown of GLS1 expression and pharmacologic GLS1 inhibition by the drug CB-839 can reduce OXPHOS, leading to leukemic cell proliferation arrest and apoptosis without causing cytotoxic activity against normal human CD34(+) progenitors. Strikingly, GLS1 knockdown dramatically inhibited AML development in NSG mice. The antileukemic activity of CB-839 was abrogated by both the expression of a hyperactive GAC(K320A) allele and the addition of the tricarboxyclic acid cycle product α-ketoglutarate, indicating the critical function of GLS1 in AML cell survival. Finally, glutaminolysis inhibition activated mitochondrial apoptosis and synergistically sensitized leukemic cells to priming with the BCL-2 inhibitor ABT-199. These findings show that targeting glutamine addiction via GLS1 inhibition offers a potential novel therapeutic strategy for AML.

Published
2015

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