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1. Maternal use of household pesticides during pregnancy and risk of neuroblastoma in offspring. A pooled analysis of the ESTELLE and ESCALE French studies (SFCE)

Author

Laurent Orsi, Marion Gambart, Brigitte Lacour, Christophe Bergeron, Paula Rios, Hélène Boutroux, Jean Michon, Estelle Thebaud, Stéphane Ducassou, Nicolas Sirvent, Helen D. Bailey, Dominique Valteau-Couanet, Jacqueline Clavel, Anne-Sophie Defachelles, Equipe 7 : EPICEA - Epidémiologie des cancers de l'enfant et de l'adolescent (CRESS - U1153), Université Paris Descartes - Paris 5 (UPD5)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Registre National des Tumeurs Solides de l'Enfant (RNTSE), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Registre National des Cancers de l'Enfant - National Registry of Childhood Cancers [Villejuif & CHU Nancy] (RNCE), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Société française de lutte contre les cancers et les leucémies de l’enfant et de l’adolescent (SFCE), Service d'Oncologie, Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), MYPAC, Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Oscar Lambert, 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 [Montpellier] (CHRU Montpellier), Département d'Oncologie Pédiatrique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), CHU de Bordeaux Pellegrin [Bordeaux], Registre National des Hémopathies malignes de l'Enfant (RNHE), and Institut de Veille Sanitaire (INVS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Pediatrics, Case–control study, Offspring, Logistic regression, Neuroblastoma, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Recall bias, Epidemiology, Odds Ratio, Humans, Medicine, Pesticides, Maternal-Fetal Exchange, business.industry, 030111 toxicology, Confounding, Case-control study, Infant, Odds ratio, medicine.disease, Logistic Models, Risk factors, Oncology, Maternal Exposure, Case-Control Studies, Child, Preschool, 030220 oncology & carcinogenesis, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, Childhood cancer, business, Demography
Abstract

International audience; Purpose: Neuroblastoma (NB) is an embryonic tumor that occurs almost exclusively in infancy and early childhood. While considerable evidence suggests that it may be initiated during embryonic development, the etiology of NB is still unknown. The aim of this study was to explore whether there is an association between maternal use of household pesticides during pregnancy and the risk of NB in the offspring.Methods: We conducted a pooled analysis of two French national-based case-control studies. The mothers of 357 NB cases and 1,783 controls younger than 6 years, frequency-matched by age and gender, responded to a telephone interview that focused on sociodemographic and perinatal characteristics, childhood environment, and life-style. Unconditional logistic regression was used to estimate pooled odds ratios and 95% confidence intervals.Results: After controlling for matching variables, study of origin, and potential confounders, the maternal use of any type of pesticide during pregnancy was associated with NB (OR 1.5 [95% CI 1.2-1.9]). The most commonly used type of pesticides were insecticides and there was a positive association with their use alone (OR 1.4 [95% CI 1.1-1.9]) or with other pesticides (OR 2.0 [95% CI 1.1-3.4]).Conclusions: Although there is the potential for recall bias due to the study design, our findings add to the evidence of an association between the household use of pesticides and NB. Until a better study design can be found, our findings add yet another reason why to advise pregnant women to limit pesticide exposure during the periconceptional period.

Published
2017

2. Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia

Author

Sonia Zaghdoudi, Guangli Yang, Lara Gales, Mathilde Cathebas, François Vergez, Héléna Boutzen, François Delhommeau, Isabelle Jouanin, Marion David, Tony Kaoma, Ouathek Ouerfelli, Pierre Hirsch, Jean-Emmanuel Sarry, Lucille Stuani, Clément Larrue, Christophe Junot, Estelle Saland, Laurent Le Cam, Romain Riscal, Laetitia K. Linares, Jean-Charles Portais, Véronique De Mas-Mansat, Eric Delabesse, Laurent Vallar, Fabienne De Toni, Florence Castelli, Christian Recher, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Etude du Métabolisme des Médicaments (LEMM), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Luxembourg Institute of Health (LIH), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Organic Synthesis Core Facility [New York, NY, USA], Memorial Sloane Kettering Cancer Center [New York], Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Laboratoire de biologie clinique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service d'immunologie et hématologies biologiques [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Analyse de Xénobiotiques, Identification, Métabolisme (E20 Metatoul-AXIOM), ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by grants from the French government under the program 'Investissement d'avenir' Cancer Pharmacology of Toulouse-Oncopole and Region (ANR-11-PHUC-001) and the project MET AML (INCA-2012-105), from the Fondation Innabiosante/Toulouse Cancer Santé, the Fondation ARC, the Association Laurette Fugain under the program RES IST AML, and the Association G.A.E.L. H. Boutzen was supported by the Fondation pour la Recherche Médicale (FDT20140930983). F. de Toni had a fellowship from the Fondation de FranceWork at the Organic Synthesis Core is partially funded through National Cancer Institute Core grant P30 CA008748-48. MetaToul is supported by grants from the Région Midi-Pyrénées, the European Regional Development Fund, the SIC OVAL, the Infrastructures en Biologie Sante et Agronomie (France), the Centre National de la Recherche Scientifique (CNRS), and the Institut National de la Recherche Agronomique (INRA)., ANR-11-PHUC-0001,CAPTOR,Cancer et Pharmacologie : Projet de Toulouse-Oncopole et de sa Région(2011), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), MetaToul AXIOM (E20), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-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)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Genomics Research Unit, Ctr Rech Publ Sante, Centre de Recherche Public de la Santé, Institut Régional du Cancer, Organic Synthesis Core Facility, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MYPAC, Université Pierre et Marie Curie (Paris 6), Pathologies biliaires, fibrose et cancer du foie (Inserm UMR_S 938), CHU Saint-Antoine [APHP]-Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), French government under the program 'Investissement d'avenir' Cancer Pharmacology of Toulouse-Oncopole and Region [ANR-11-PHUC-001], project MET AML [INCA-2012-105], Fondation Innabiosante/Toulouse Cancer Sante, Fondation ARC, Association Laurette Fugain under the program RES IST AML, Association G.A.E.L., Fondation pour la Recherche Medicale [FDT20140930983], Fondation de FranceWork at the Organic Synthesis Core through National Cancer Institute [P30 CA008748-48], Region Midi-Pyrenee s, European Regional Development Fund, SIC OVAL, Infrastructures en Biologie Sante et Agronomie (France), Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], CRLCC Henri Becquerel-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Service d'immunologie et hématologies biologiques [Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Sorbonne Université (SU)-CHU Saint-Antoine [APHP], Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), ANR-11-PHUC-0001/11-PHUC-0001,CAPTOR,Cancer et Pharmacologie : Projet de Toulouse-Oncopole et de sa Région(2011), Linares, Laetitia, Pôle hospitalier Universitaire Cancer (PHUC) - Cancer et Pharmacologie : Projet de Toulouse-Oncopole et de sa Région - - CAPTOR2011 - ANR-11-PHUC-0001 - PHUC - VALID, Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-MetaboHUB-MetaToul, Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
Male, gene set enrichment analysis, IDH, 0301 basic medicine, Myeloid, Abbreviations used: 2-HG, [SDV]Life Sciences [q-bio], Mutant, Retinoic acid, gene set enrich, Mice, chemistry.chemical_compound, 0302 clinical medicine, NBT, AML, hemic and lymphatic diseases, retinoic acid, Immunology and Allergy, L-CFU, promyelocytic leukemia, ATRA, promyelocytic l, Research Articles, transcription factor, all-trans RA, BCL, Myeloid leukemia, Cell Differentiation, Isocitrate Dehydrogenase, Neoplasm Proteins, quantitative Ch, 3. Good health, chromatin immun, Leukemia, Myeloid, Acute, qPCR, Leukemia, Haematopoiesis, qChIP, medicine.anatomical_structure, Isocitrate dehydrogenase, 030220 oncology & carcinogenesis, Female, 2-hydroxyglutar, TF, liquid chromato, α-KG, quantitative ChIP, IDH1, Cell Survival, Immunology, Mutation, Missense, ChIP, Mice, Nude, 2-hydroxyglutarate, HL-60 Cells, Tretinoin, [SDV.CAN]Life Sciences [q-bio]/Cancer, chromatin immunoprecipitation, acute myeloid leukemia, Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, nitrotetrazolium blue, quantitative PC, medicine, Animals, Humans, isocitrate de-, neoplasms, liquid chromatography-mass spectrometry, GSEA, nitrotetrazoliu, PML, Brief Definitive Report, LC/MS, transcription f, acute PML, medicine.disease, Xenograft Model Antitumor Assays, B cell lymphoma, APL, α-ketoglutarate, 030104 developmental biology, Amino Acid Substitution, chemistry, isocitrate de- hydrogenase, quantitative PCR, CCAAT-Enhancer-Binding Proteins, Cancer research, acute myeloid l, leukemic CFU, Blast Crisis, Abbreviations u, RA, Granulocytes
Abstract

Boutzen et al. show that the IDH1 mutation and its oncometabolite, (R)-2-hydroxyglutarate, dysregulate downstream target pathways of myeloid-specific TFs, especially CEBPα, priming mutant IDH1-R132H AML blasts to the granulomonocytic lineage., Acute myeloid leukemia (AML) is characterized by the accumulation of malignant blasts with impaired differentiation programs caused by recurrent mutations, such as the isocitrate dehydrogenase (IDH) mutations found in 15% of AML patients. These mutations result in the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG), leading to a hypermethylation phenotype that dysregulates hematopoietic differentiation. In this study, we identified mutant R132H IDH1-specific gene signatures regulated by key transcription factors, particularly CEBPα, involved in myeloid differentiation and retinoid responsiveness. We show that treatment with all-trans retinoic acid (ATRA) at clinically achievable doses markedly enhanced terminal granulocytic differentiation in AML cell lines, primary patient samples, and a xenograft mouse model carrying mutant IDH1. Moreover, treatment with a cell-permeable form of 2-HG sensitized wild-type IDH1 AML cells to ATRA-induced myeloid differentiation, whereas inhibition of 2-HG production significantly reduced ATRA effects in mutant IDH1 cells. ATRA treatment specifically decreased cell viability and induced apoptosis of mutant IDH1 blasts in vitro. ATRA also reduced tumor burden of mutant IDH1 AML cells xenografted in NOD–Scid–IL2rγnull mice and markedly increased overall survival, revealing a potent antileukemic effect of ATRA in the presence of IDH1 mutation. This therapeutic strategy holds promise for this AML patient subgroup in future clinical studies.

Published
2016

3. SNP-array lesions in core binding factor acute myeloid leukemia

Author

Duployez, Nicolas, Boudry-Labis, Elise, Roumier, Christophe, Boissel, Nicolas, Petit, Arnaud, Geffroy, Sandrine, Helevaut, Nathalie, Celli-Lebras, Karine, Terré, Christine, Fenneteau, Odile, Cuccuini, Wendy, Luquet, Isabelle, Lapillonne, Hélène, Lacombe, Catherine, Cornillet, Pascale, Ifrah, Norbert, Dombret, Hervé, Leverger, Guy, Jourdan, Eric, Preudhomme, Claude, Bernardo, Elizabeth, Laboratoire d'Hématologie [CHRU Lille] (Centre de Biologie et de Pathologie), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut de Génétique Médicale [CHRU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Hématologie [AP-HP Hôpital Saint-Louis], 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), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université (SU), CHU Trousseau [APHP], Département de Génétique [CH Versailles], Centre Hospitalier de Versailles André Mignot (CHV), Laboratoire d'Hématologie [AP-HP Hôpital Robert Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Département de Cytogénétique [AP-HP Hôpital Saint-Louis], Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Goelamsthèque [AP-HP Hôpital Cochin], Hôpital Cochin [AP-HP], Laboratoire d'Hématologie [CHU Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), 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), Département d'Hématologie [CHU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'Hématologie [Rangueil], Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], 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), Laboratoire d'Hématologie [CHRU Lille] ( Centre de Biologie et de Pathologie ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc) - U1172 ( JPArc ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), AP-HP Hôpital Saint-Louis, Groupe de Recherche Clinique n°7 - Myéloproliférations aiguës et chroniques [AP-HP Hôpital Saint-Antoine] ( GRC n°07 - MyPAC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -AP-HP - Hôpital Saint-Antoine, Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Sorbonne Universités, Département d'Hématologie et d'Oncologie Pédiatrique [AP-HP Hôpitaux universitaires Est parisien], Groupe Hospitalier des Hôpitaux Universitaires de l’Est Parisien-AP-HP Hôpital Armand-Trousseau [Paris], Centre Hospitalier de Versailles (CHV), Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital de Rangueil, Laboratoire d'Hématologie [AP-HP Hôpitaux universitaires Est parisien], AP-HP Hôpital cochin, Centre Hospitalier Universitaire de Reims ( CHU Reims ), Innate immunity and Immunotherapy ( CRCINA - Département INCIT - Equipe 7 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), 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 ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -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 ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), and Centre Hospitalier Universitaire de Nîmes ( CHU de Nîmes )

Subjects
SNP-array, [SDV.CAN] Life Sciences [q-bio]/Cancer, hemic and lymphatic diseases, [SDV.CAN]Life Sciences [q-bio]/Cancer, sequencing, acute myeloid leukemia, core binding factor, [ SDV.CAN ] Life Sciences [q-bio]/Cancer
Abstract

International audience; Acute myeloid leukemia (AML) with t(8;21) and inv(16), together referred as core binding factor (CBF)-AML, are recognized as unique entities. Both rearrangements share a common pathophysiology, the disruption of the CBF, and a relatively good prognosis. Experiments have demonstrated that CBF rearrangements were insufficient to induce leukemia, implying the existence of cooperating events. To explore these aberrations, we performed single nucleotide polymorphism (SNP)-array in a well-annotated cohort of 198 patients with CBF-AML. Excluding breakpoint-associated lesions, the most frequent events included loss of a sex chromosome (53%), deletions at 9q21 (12%) and 7q36 (9%) in patients with t(8;21) compared with trisomy 22 (13%), trisomy 8 (10%) and 7q36 deletions (12%) in patients with inv(16). SNP-array revealed novel recurrent genetic alterations likely to be involved in CBF-AML leukemogenesis. ZBTB7A mutations (20% of t(8;21)-AML) were shown to be a target of copy-neutral losses of heterozygosity (CN-LOH) at chromosome 19p. FOXP1 focal deletions were identified in 5% of inv(16)-AML while sequence analysis revealed that 2% carried FOXP1 truncating mutations. Finally, CCDC26 disruption was found in both subtypes (4.5% of the whole cohort) and possibly highlighted a new lesion associated with aberrant tyrosine kinase signaling in this particular subtype of leukemia.

Published
2018

4. Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143)

Author

Yanyan Zhang, Yin Gu, Patrick Lappin, Ollivier Legrand, Flavia Pernasetti, Fawzia Louache, Tod Smeal, Valeria Fantin, François Delhommeau, Stéphane de Botton, Shu-Hui Liu, Dusko Trajkovic, Ruoping Tang, Erika Saavedra, HAL UPMC, Gestionnaire, CNRS GDR 3697 MicroNiT, Centre National de la Recherche Scientifique (CNRS), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), MYPAC, Université Pierre et Marie Curie - Paris 6 (UPMC), Pfizer Oncology, Pfizer, Département d'hématologie [Gustave Roussy], Faculte de Medecine, Université Paris-Sud - Paris 11 (UP11), CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Receptors, CXCR4, Myeloid, Science, Primary Cell Culture, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, CXCR4, Article, Mice, 03 medical and health sciences, Antineoplastic Agents, Immunological, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Movement, Cell Line, Tumor, hemic and lymphatic diseases, Animals, Humans, Medicine, Molecular Targeted Therapy, Progenitor cell, Multidisciplinary, CXCR4 antagonist, business.industry, Chemotaxis, Antibody-Dependent Cell Cytotoxicity, Antibodies, Monoclonal, Myeloid leukemia, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Xenograft Model Antitumor Assays, 3. Good health, Transplantation, Disease Models, Animal, Leukemia, Myeloid, Acute, Leukemia, 030104 developmental biology, medicine.anatomical_structure, Immunology, Cancer research, Bone marrow, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business
Abstract

The chemokine receptor CXCR4 mediates cell anchorage in the bone marrow (BM) microenvironment and is overexpressed in 25–30% of patients with acute myeloid leukemia (AML). Here we have shown that a new CXCR4 receptor antagonist IgG1 antibody (PF-06747143) binds strongly to AML cell lines and to AML primary cells inhibiting their chemotaxis in response to CXCL12. PF-06747143 also induced cytotoxicity in AML cells via Fc-effector function. To characterize the effects of PF-06747143 on leukemia progression, we used two different patient-derived xenograft (PDX) models: Patient 17CXCR4-low and P15CXCR4-high models, characterized by relatively low and high CXCR4 expression, respectively. Weekly administration of PF-06747143 to leukemic mice significantly reduced leukemia development in both models. Secondary transplantation of BM cells from PF-06747143-treated or IgG1 control-treated animals showed that leukemic progenitors were also targeted by PF-06747143. Administration of a single dose of PF-06747143 to PDX models induced rapid malignant cell mobilization into the peripheral blood (PB). These findings support evaluation of this antibody in AML therapy, with particular appeal to patients resistant to chemotherapy and to unfit patients, unable to tolerate intensive chemotherapy.

Published
2017

5. Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia

Author

Hannah Moatti, François Delhommeau, Rémi Favier, Mohamad Mohty, Chrystele Bilhou-Nabera, Fawzia Louache, Virginie Joulin, Ruoping Tang, Aline Betems, Elodie Pronier, Florence Lorre, Pascale Flandrin, Ollivier Legrand, Fanny Fava, Christophe Marzac, Pierre Hirsch, Frédéric Féger, Hélène Boutroux, Hayat Mokrani, Luc Douay, Dominique Bories, Yanyan Zhang, Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), MYPAC, Université Pierre et Marie Curie - Paris 6 (UPMC), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Gustave Roussy (IGR), CHU Saint-Antoine [AP-HP], Hématologie moléculaire [CHU Mondor], CHU Henri Mondor, Laboratoire commun de biologie et génétique moléculaires [CHU Saint-Antoine], and CHU Henri Mondor [Créteil]

Subjects
0301 basic medicine, Time Factors, Myeloid, Science, Clone (cell biology), General Physics and Astronomy, Biology, medicine.disease_cause, Somatic evolution in cancer, Article, General Biochemistry, Genetics and Molecular Biology, Epigenesis, Genetic, Clonal Evolution, Mice, 03 medical and health sciences, hemic and lymphatic diseases, medicine, Animals, Humans, neoplasms, Variegation, Gene Rearrangement, [SDV.GEN]Life Sciences [q-bio]/Genetics, Mutation, Multidisciplinary, Base Sequence, General Chemistry, Gene rearrangement, medicine.disease, Clone Cells, Hematopoiesis, Leukemia, Myeloid, Acute, Leukemia, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, Immunology, Single-Cell Analysis
Abstract

In acute myeloid leukaemia (AML) initiating pre-leukaemic lesions can be identified through three major hallmarks: their early occurrence in the clone, their persistence at relapse and their ability to initiate multilineage haematopoietic repopulation and leukaemia in vivo. Here we analyse the clonal composition of a series of AML through these characteristics. We find that not only DNMT3A mutations, but also TET2, ASXL1 mutations, core-binding factor and MLL translocations, as well as del(20q) mostly fulfil these criteria. When not eradicated by AML treatments, pre-leukaemic cells with these lesions can re-initiate the leukaemic process at various stages until relapse, with a time-dependent increase in clonal variegation. Based on the nature, order and association of lesions, we delineate recurrent genetic hierarchies of AML. Our data indicate that first lesions, variegation and treatment selection pressure govern the expansion and adaptive behaviour of the malignant clone, shaping AML in a time-dependent manner., Pre-leukaemic clones, together with the propensity to cause disease in mice, are characterized by appearing early in myeloid leukaemia and being found at relapse. Here, the authors identify clones in human samples and find that they are characterized by hierarchically organized genetic lesions, which can be used to track evolution of the disease.

Published
2016

6. A web-based delphi study for eliciting helpful criteria in the positive diagnosis of hemophagocytic syndrome in adult patients

Author

Olivier Lambotte, Paul Coppo, Christophe Marzac, Lionel Galicier, Gilles Hejblum, Cedric Aumont, Laurence Fardet, Pôle de Pharmacie - Santé Publique - Information médicale [Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11), Médecine interne [CHU Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Immunologie clinique [CHU St-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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), MYPAC, Hématologie biologique [CHU Bicêtre], HAL UPMC, Gestionnaire, Pôle de Pharmacie - Santé Publique - Information médicale [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Pediatrics, Delphi Technique, Epidemiology, Delphi method, lcsh:Medicine, Computer Applications, Surveys and Questionnaires, Medicine and Health Sciences, Medicine, Clinical Epidemiology, lcsh:Science, Immune Response, Multidisciplinary, Applied Mathematics, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Pancytopenia, 3. Good health, Research Design, Physical Sciences, [SDV.IMM]Life Sciences [q-bio]/Immunology, Hemophagocytosis, medicine.symptom, Statistics (Mathematics), Tissue biopsy, Research Article, Adult, medicine.medical_specialty, Computer and Information Sciences, Consensus, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, MEDLINE, Research and Analysis Methods, Organomegaly, Lymphohistiocytosis, Hemophagocytic, Immune Activation, Decision Theory, Diagnostic Medicine, Humans, Cytopenia, Internet, Survey Research, Adult patients, business.industry, lcsh:R, Immunity, Biology and Life Sciences, medicine.disease, Survey Methods, lcsh:Q, Clinical Immunology, business, Mathematics
Abstract

International audience; The diagnosis of the reactive form of hemophagocytic syndrome in adults remains particularly difficult since none of the clinical or laboratory manifestations are specific. We undertook a study in order to elicit which features constitute helpful criteria for a positive diagnosis. In this Delphi study, the features investigated in the questionnaire and the experts invited to participate in the survey were issued from a bibliographic search. The questionnaire was iteratively proposed to experts via a web-based application with a feedback of the results observed at the preceding Delphi round. Experts were asked to label each investigated criterion in one of the following categories: absolutely required, important, of minor interest, or not assessable in the routine practice environment. A positive consensus was a priori defined as at least 75% answers observed in the categories absolutely required and important. The questionnaire investigated 26 criteria and 24 experts originating from 13 countries participated in the second and final Delphi round. A positive consensus was reached for the nine following criteria: unilineage cytopenia, bicytopenia, pancytopenia, presence of hemophagocytosis pictures on a bone marrow aspirate or on a tissue biopsy, high ferritin level, fever, organomegaly, presence of a predisposing underlying disease, and high level of lactate dehydrogenase. A negative consensus was reached for 13 criteria, and an absence of consensus was observed for 4 criteria. The study constitutes the first initiative to date for defining international guidelines devoted to the positive diagnosis of the reactive form of hemophagocytic syndrome.

Published
2013

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

Author

Steimlé T, Dourthe ME, Alcantara M, Touzart A, Simonin M, Mondesir J, Lhermitte L, Bond J, Graux C, Grardel N, Cayuela JM, Arnoux I, Gandemer V, Balsat M, Vey N, Macintyre E, Ifrah N, Dombret H, Petit A, Baruchel A, Ruminy P, Boissel N, and Asnafi V

Subjects
Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Male, Middle Aged, Young Adult, Prognosis, T-Lymphocytes pathology, Oncogene Proteins, Fusion genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology
Abstract

T-cell acute lymphoblastic leukemias (T-ALL) represent 15% of pediatric and 25% of adult ALL. Since they have a particularly poor outcome in relapsed/refractory cases, identifying prognosis factors at diagnosis is crucial to adapting treatment for high-risk patients. Unlike acute myeloid leukemia and BCP ALL, chromosomal rearrangements leading to chimeric fusion-proteins with strong prognosis impact are sparsely reported in T-ALL. To address this issue an RT-MPLA assay was applied to a consecutive series of 522 adult and pediatric T-ALLs and identified a fusion transcript in 20% of cases. PICALM-MLLT10 (4%, n = 23), NUP214-ABL1 (3%, n = 19) and SET-NUP214 (3%, n = 18) were the most frequent. The clinico-biological characteristics linked to fusion transcripts in a subset of 235 patients (138 adults in the GRAALL2003/05 trials and 97 children from the FRALLE2000 trial) were analyzed to identify their prognosis impact. Patients with HOXA trans-deregulated T-ALLs with MLLT10, KMT2A and SET fusion transcripts (17%, 39/235) had a worse prognosis with a 5-year EFS of 35.7% vs 63.7% (HR = 1.63; p = 0.04) and a trend for a higher cumulative incidence of relapse (5-year CIR = 45.7% vs 25.2%, HR = 1.6; p = 0.11). Fusion transcripts status in T-ALL can be robustly identified by RT-MLPA, facilitating risk adapted treatment strategies for high-risk patients., (© 2022. The Author(s).)

Published
2022
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9. IKZF1 alterations predict poor prognosis in adult and pediatric T-ALL.

Author

Simonin M, Lhermitte L, Dourthe ME, Lengliné E, Graux C, Grardel N, Cayuela JM, Arnoux I, Gandemer V, Ifrah N, Dombret H, Baruchel A, Macintyre E, Petit A, Boissel N, and Asnafi V

Subjects
Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Male, Middle Aged, Mutation, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Prognosis, Young Adult, Ikaros Transcription Factor genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics
Published
2021
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10. Safety and Efficacy of Fidaxomicin and Vancomycin in Children and Adolescents with Clostridioides (Clostridium) difficile Infection: A Phase 3, Multicenter, Randomized, Single-blind Clinical Trial (SUNSHINE).

Author

Wolf J, Kalocsai K, Fortuny C, Lazar S, Bosis S, Korczowski B, Petit A, Bradford D, Croos-Dabrera R, Incera E, Melis J, and van Maanen R

Subjects
Adolescent, Adult, Aged, Aminoglycosides adverse effects, Anti-Bacterial Agents adverse effects, Child, Child, Preschool, Clostridioides, Clostridium, Fidaxomicin, Humans, Single-Blind Method, Treatment Outcome, Vancomycin adverse effects, Clostridioides difficile, Clostridium Infections drug therapy
Abstract

Background: Fidaxomicin, a narrow-spectrum antibiotic approved for Clostridioides (Clostridium) difficile infection (CDI) in adults, is associated with lower rates of recurrence than vancomycin; however, pediatric data are limited. This multicenter, investigator-blind, phase 3, parallel-group trial assessed the safety and efficacy of fidaxomicin in children., Methods: Patients aged <18 years with confirmed CDI were randomized 2:1 to 10 days of treatment with fidaxomicin (suspension or tablets, twice daily) or vancomycin (suspension or tablets, 4 times daily). Safety assessments included treatment-emergent adverse events. The primary efficacy end point was confirmed clinical response (CCR), 2 days after the end of treatment (EOT). Secondary end points included global cure (GC; CCR without CDI recurrence) 30 days after EOT (end of study; EOS). Plasma and stool concentrations of fidaxomicin and its active metabolite OP-1118 were measured., Results: Of 148 patients randomized, 142 were treated (30 <2 years old). The proportion of participants with treatment-emergent adverse events was similar with fidaxomicin (73.5%) and vancomycin (75.0%). Of 3 deaths in the fidaxomicin arm during the study, none were CDI or treatment related. The rate of CCR at 2 days after EOT was 77.6% (76 of 98 patients) with fidaxomicin and 70.5% (31 of 44) with vancomycin, whereas the rate of GC at EOS was significantly higher in participants receiving fidaxomicin (68.4% vs 50.0%; adjusted treatment difference, 18.8%; 95% confidence interval, 1.5%-35.3%). Systemic absorption of fidaxomicin and OP-1118 was minimal, and stool concentrations were high., Conclusions: Compared with vancomycin, fidaxomicin was well tolerated and demonstrated significantly higher rates of GC in children and adolescents with CDI., Clinical Trials Registration: NCT02218372., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Published
2020
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11. Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-cell acute lymphoblastic leukemia.

Author

Petit A, Trinquand A, Chevret S, Ballerini P, Cayuela JM, Grardel N, Touzart A, Brethon B, Lapillonne H, Schmitt C, Thouvenin S, Michel G, Preudhomme C, Soulier J, Landman-Parker J, Leverger G, Macintyre E, Baruchel A, and Asnafi V

Subjects
Adolescent, Child, Child, Preschool, Disease-Free Survival, Genes, Neoplasm, Humans, Infant, Infant, Newborn, Leukocyte Count, Neoplasm, Residual blood, Prognosis, Recurrence, Treatment Outcome, Mutation genetics, Neoplasm, Residual genetics, Oncogenes genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics
Abstract

Risk stratification in childhood T-cell acute lymphoblastic leukemia (T-ALL) is mainly based on minimal residual disease (MRD) quantification. Whether oncogenetic mutation profiles can improve the discrimination of MRD-defined risk categories was unknown. Two hundred and twenty FRALLE2000T-treated patients were tested retrospectively for NOTCH1/FBXW7/RAS and PTEN alterations. Patients with NOTCH1/FBXW7 ( N/F ) mutations and RAS/PTEN ( R/P ) germ line (GL) were classified as oncogenetic low risk (gLoR; n = 111), whereas those with N/F GL and R/P GL mutations or N/F and R/P mutations were classified as high risk (gHiR; n = 109). Day 35 MRD status was available for 191 patients. Five-year cumulative incidence of relapse (CIR) and disease-free survival were 36% and 60% for gHiR patients and 11% and 89% for gLoR patients, respectively. Importantly, among the 60% of patients with MRD <10 -4 , 5-year CIR was 29% for gHiR patients and 4% for gLoR patients. Based on multivariable Cox models and stepwise selection, the 3 most discriminating variables were the oncogenetic classifier, MRD, and white blood cell (WBC) count. Patients harboring a WBC count ≥200 × 10 9 /L, gHiR classifier, and MRD ≥10 -4 demonstrated a 5-year CIR of 46%, whereas the 58 patients (30%) with a WBC count <200 × 10 9 /L, gLoR classifier, and MRD <10 -4 had a very low risk of relapse, with a 5-year CIR of only 2%. In childhood T-ALL, the N/F/R/P mutation profile is an independent predictor of relapse. When combined with MRD and a WBC count ≥200 × 10 9 /L, it identifies a significant subgroup of patients with a low risk of relapse., (© 2018 by The American Society of Hematology.)

Published
2018
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12. SNP-array lesions in core binding factor acute myeloid leukemia.

Author

Duployez N, Boudry-Labis E, Roumier C, Boissel N, Petit A, Geffroy S, Helevaut N, Celli-Lebras K, Terré C, Fenneteau O, Cuccuini W, Luquet I, Lapillonne H, Lacombe C, Cornillet P, Ifrah N, Dombret H, Leverger G, Jourdan E, and Preudhomme C

Abstract

Acute myeloid leukemia (AML) with t(8;21) and inv(16), together referred as core binding factor (CBF)-AML, are recognized as unique entities. Both rearrangements share a common pathophysiology, the disruption of the CBF, and a relatively good prognosis. Experiments have demonstrated that CBF rearrangements were insufficient to induce leukemia, implying the existence of cooperating events. To explore these aberrations, we performed single nucleotide polymorphism (SNP)-array in a well-annotated cohort of 198 patients with CBF-AML. Excluding breakpoint-associated lesions, the most frequent events included loss of a sex chromosome (53%), deletions at 9q21 (12%) and 7q36 (9%) in patients with t(8;21) compared with trisomy 22 (13%), trisomy 8 (10%) and 7q36 deletions (12%) in patients with inv(16). SNP-array revealed novel recurrent genetic alterations likely to be involved in CBF-AML leukemogenesis. ZBTB7A mutations (20% of t(8;21)-AML) were shown to be a target of copy-neutral losses of heterozygosity (CN-LOH) at chromosome 19p. FOXP1 focal deletions were identified in 5% of inv(16)-AML while sequence analysis revealed that 2% carried FOXP1 truncating mutations. Finally, CCDC26 disruption was found in both subtypes (4.5% of the whole cohort) and possibly highlighted a new lesion associated with aberrant tyrosine kinase signaling in this particular subtype of leukemia., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Published
2018
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14. Selective testing for calreticulin gene mutations in patients with splanchnic vein thrombosis: A prospective cohort study.

Author

Poisson J, Plessier A, Kiladjian JJ, Turon F, Cassinat B, Andreoli A, De Raucourt E, Goria O, Zekrini K, Bureau C, Lorre F, Cervantes F, Colomer D, Durand F, Garcia-Pagan JC, Casadevall N, Valla DC, Rautou PE, and Marzac C

Subjects
Adult, Female, Humans, Janus Kinase 2 genetics, Male, Middle Aged, Myeloproliferative Disorders genetics, Prospective Studies, Calreticulin genetics, Mutation, Venous Thrombosis genetics
Abstract

Background and Aims: Myeloproliferative neoplasms (MPN) are the leading cause of splanchnic vein thrombosis (SVT). Janus kinase 2 gene (JAK2) V617F mutations are found in 80 to 90% of patients with SVT and MPN. Mutations of the calreticulin (CALR) gene have also been reported. However, as their prevalence ranges from 0 to 2%, the utility of routine testing is questionable. This study aimed to identify a group of patients with SVT at high risk of harboring CALR mutations and thus requiring this genetic testing., Methods: CALR, JAK2 V617F and thrombopoietin receptor gene (MPL) mutations were analysed in a test cohort that included 312 patients with SVT. Criteria to identify patients at high risk of CALR mutations in this test cohort was used and evaluated in a validation cohort that included 209 patients with SVT., Results: In the test cohort, 59 patients had JAK2 V617F , five had CALR and none had MPL mutations. Patients with CALR mutations had higher spleen height and platelet count than patients without these mutations. All patients with CALR mutations had a spleen height ⩾16cm and platelet count >200×10 9 /L. These criteria had a positive predictive value of 56% (5/9) and a negative predictive value of 100% (0/233) for the identification of CALR mutations. In the validation cohort, these criteria had a positive predictive value of 33% (2/6) and a negative predictive value of 99% (1/96)., Conclusion: CALR mutations should be tested in patients with SVT, a spleen height ⩾16cm, platelet count >200×10 9 /L, and no JAK2 V617F . This strategy avoids 96% of unnecessary CALR mutations testing. Lay summary: Mutations of the CALR gene are detected in 0 to 2% of patients with SVT, thus the utility of systematic CALR mutation testing to diagnose MPN is questionable. This study demonstrates that CALR mutations testing can be restricted to patients with SVT, a spleen height ⩾16cm, a platelet count >200×10 9 /L, and no JAK2 V617F . This strategy avoids 96% of unnecessary CALR mutations testing., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Published
2017
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15. Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143).

Author

Zhang Y, Saavedra E, Tang R, Gu Y, Lappin P, Trajkovic D, Liu SH, Smeal T, Fantin V, De Botton S, Legrand O, Delhommeau F, Pernasetti F, and Louache F

Subjects
Animals, Antibody-Dependent Cell Cytotoxicity immunology, Apoptosis drug effects, Cell Line, Tumor, Cell Movement drug effects, Chemotaxis drug effects, Chemotaxis immunology, Disease Models, Animal, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute immunology, Leukemia, Myeloid, Acute mortality, Mice, Molecular Targeted Therapy, Primary Cell Culture, Receptors, CXCR4 genetics, Receptors, CXCR4 metabolism, Xenograft Model Antitumor Assays, Antibodies, Monoclonal pharmacology, Antineoplastic Agents, Immunological pharmacology, Leukemia, Myeloid, Acute metabolism, Receptors, CXCR4 antagonists & inhibitors
Abstract

The chemokine receptor CXCR4 mediates cell anchorage in the bone marrow (BM) microenvironment and is overexpressed in 25-30% of patients with acute myeloid leukemia (AML). Here we have shown that a new CXCR4 receptor antagonist IgG1 antibody (PF-06747143) binds strongly to AML cell lines and to AML primary cells inhibiting their chemotaxis in response to CXCL12. PF-06747143 also induced cytotoxicity in AML cells via Fc-effector function. To characterize the effects of PF-06747143 on leukemia progression, we used two different patient-derived xenograft (PDX) models: Patient 17 CXCR4-low and P15 CXCR4-high models, characterized by relatively low and high CXCR4 expression, respectively. Weekly administration of PF-06747143 to leukemic mice significantly reduced leukemia development in both models. Secondary transplantation of BM cells from PF-06747143-treated or IgG1 control-treated animals showed that leukemic progenitors were also targeted by PF-06747143. Administration of a single dose of PF-06747143 to PDX models induced rapid malignant cell mobilization into the peripheral blood (PB). These findings support evaluation of this antibody in AML therapy, with particular appeal to patients resistant to chemotherapy and to unfit patients, unable to tolerate intensive chemotherapy.

Published
2017
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16. Expression of CD94 by ex vivo -differentiated NK cells correlates with the in vitro and in vivo acquisition of cytotoxic features.

Author

Hasmim M, Khalife N, Zhang Y, Doldur M, Visentin G, Terry S, Giron-Michel J, Tang R, Delhommeau F, Dulphy N, Bourhis JH, Louache F, and Chouaib S

Abstract

The administration of ex vivo -expanded Natural Killer (NK) cells in leukemia therapy is still challenging, in part due to the difficulty to generate in sufficient quantities fully mature and functional NK cells and Identification of surface markers indicative of NK maturation and functionality is therefore needed. Here, based on the analysis of surface receptors of ex vivo -expanded NK cells, we identified CD94 as a surface marker correlating with high lytic potential against leukemic cell lines and immunological synapse formation. CD94-positive ex vivo -expanded NK cells displayed higher expression of NKG2 receptors and the adhesion molecule LFA-1, as compared with their CD94-negative counterparts. We also tested the in vivo anti-leukemic capacity of ex vivo -expanded NK cells against patient-derived acute myeloid leukemia cells. Although no anti-leukemic effect was detected, we noticed that only CD94-positive ex vivo -expanded NK cells were detected in leukemic mice at the end of the 2-week treatment. Moreover, flow cytometry analysis showed a subpopulation harboring CD94 (NK) and CD34 (leukemic cells) double staining, indicative of conjugate formation. Therefore surface expression of CD94 on ex vivo -differentiated NK cells emerged as an indicator of in vitro and in vivo killer cell functionality.

Published
2017
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17. Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism.

Author

Farge T, Saland E, de Toni F, Aroua N, Hosseini M, Perry R, Bosc C, Sugita M, Stuani L, Fraisse M, Scotland S, Larrue C, Boutzen H, Féliu V, Nicolau-Travers ML, Cassant-Sourdy S, Broin N, David M, Serhan N, Sarry A, Tavitian S, Kaoma T, Vallar L, Iacovoni J, Linares LK, Montersino C, Castellano R, Griessinger E, Collette Y, Duchamp O, Barreira Y, Hirsch P, Palama T, Gales L, Delhommeau F, Garmy-Susini BH, Portais JC, Vergez F, Selak M, Danet-Desnoyers G, Carroll M, Récher C, and Sarry JE

Subjects
Animals, CD36 Antigens genetics, Cell Line, Tumor, Cell Lineage drug effects, Cell Lineage genetics, Cytarabine adverse effects, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Mice, Mitochondria metabolism, Mitochondria pathology, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells pathology, Oxidative Phosphorylation drug effects, Xenograft Model Antitumor Assays, Cytarabine administration & dosage, Drug Resistance, Neoplasm drug effects, Leukemia, Myeloid, Acute drug therapy, Mitochondria drug effects
Abstract

Chemotherapy-resistant human acute myeloid leukemia (AML) cells are thought to be enriched in quiescent immature leukemic stem cells (LSC). To validate this hypothesis in vivo , we developed a clinically relevant chemotherapeutic approach treating patient-derived xenografts (PDX) with cytarabine (AraC). AraC residual AML cells are enriched in neither immature, quiescent cells nor LSCs. Strikingly, AraC-resistant preexisting and persisting cells displayed high levels of reactive oxygen species, showed increased mitochondrial mass, and retained active polarized mitochondria, consistent with a high oxidative phosphorylation (OXPHOS) status. AraC residual cells exhibited increased fatty-acid oxidation, upregulated CD36 expression, and a high OXPHOS gene signature predictive for treatment response in PDX and patients with AML. High OXPHOS but not low OXPHOS human AML cell lines were chemoresistant in vivo. Targeting mitochondrial protein synthesis, electron transfer, or fatty-acid oxidation induced an energetic shift toward low OXPHOS and markedly enhanced antileukemic effects of AraC. Together, this study demonstrates that essential mitochondrial functions contribute to AraC resistance in AML and are a robust hallmark of AraC sensitivity and a promising therapeutic avenue to treat AML residual disease. Significance: AraC-resistant AML cells exhibit metabolic features and gene signatures consistent with a high OXPHOS status. In these cells, targeting mitochondrial metabolism through the CD36-FAO-OXPHOS axis induces an energetic shift toward low OXPHOS and strongly enhanced antileukemic effects of AraC, offering a promising avenue to design new therapeutic strategies and fight AraC resistance in AML. Cancer Discov; 7(7); 716-35. ©2017 AACR. See related commentary by Schimmer, p. 670 This article is highlighted in the In This Issue feature, p. 653 ., (©2017 American Association for Cancer Research.)

Published
2017
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18. Precision and prognostic value of clone-specific minimal residual disease in acute myeloid leukemia.

Author

Hirsch P, Tang R, Abermil N, Flandrin P, Moatti H, Favale F, Suner L, Lorre F, Marzac C, Fava F, Mamez AC, Lapusan S, Isnard F, Mohty M, Legrand O, Douay L, Bilhou-Nabera C, and Delhommeau F

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Biomarkers, Tumor, Chromosome Aberrations, Female, High-Throughput Nucleotide Sequencing, Humans, In Situ Hybridization, Fluorescence, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Mutation, Precision Medicine, Prognosis, Young Adult, Clonal Evolution genetics, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Neoplasm, Residual diagnosis, Neoplasm, Residual genetics
Abstract

The genetic landscape of adult acute myeloid leukemias (AML) has been recently unraveled. However, due to their genetic heterogeneity, only a handful of markers are currently used for the evaluation of minimal residual disease (MRD). Recent studies using multi-target strategies indicate that detection of residual mutations in less than 5% of cells in complete remission is associated with a better survival. Here, in a series of 69 AMLs with known clonal architecture, we design a clone-specific strategy based on fluorescent in situ hybridization and high-sensitivity next generation sequencing to detect chromosomal aberrations and mutations, respectively, in follow-up samples. The combination of these techniques allows tracking chromosomal and genomic lesions down to 0.5-0.4% of the cell population in remission samples. By testing all lesions in follow-up samples from 65 of 69 evaluable patients, we find that initiating events often persist and appear to be, on their own, inappropriate markers to predict short-term relapse. In contrast, the persistence of two or more lesions in more than 0.4% of the cells from remission samples is strongly associated with lower leukemia-free and overall survivals in univariate and multivariate analyses. Although larger prospective studies are needed to extend these results, our data show that a personalized, clone-specific, MRD follow up strategy is feasible in the vast majority of AML cases., (Copyright© 2017 Ferrata Storti Foundation.)

Published
2017
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19. Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia.

Author

Hirsch P, Zhang Y, Tang R, Joulin V, Boutroux H, Pronier E, Moatti H, Flandrin P, Marzac C, Bories D, Fava F, Mokrani H, Betems A, Lorre F, Favier R, Féger F, Mohty M, Douay L, Legrand O, Bilhou-Nabera C, Louache F, and Delhommeau F

Subjects
Animals, Base Sequence, Clone Cells, Epigenesis, Genetic, Gene Rearrangement genetics, Hematopoiesis, Humans, Mice, Mutation genetics, Single-Cell Analysis, Time Factors, Clonal Evolution genetics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology
Abstract

In acute myeloid leukaemia (AML) initiating pre-leukaemic lesions can be identified through three major hallmarks: their early occurrence in the clone, their persistence at relapse and their ability to initiate multilineage haematopoietic repopulation and leukaemia in vivo. Here we analyse the clonal composition of a series of AML through these characteristics. We find that not only DNMT3A mutations, but also TET2, ASXL1 mutations, core-binding factor and MLL translocations, as well as del(20q) mostly fulfil these criteria. When not eradicated by AML treatments, pre-leukaemic cells with these lesions can re-initiate the leukaemic process at various stages until relapse, with a time-dependent increase in clonal variegation. Based on the nature, order and association of lesions, we delineate recurrent genetic hierarchies of AML. Our data indicate that first lesions, variegation and treatment selection pressure govern the expansion and adaptive behaviour of the malignant clone, shaping AML in a time-dependent manner.

Published
2016
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20. Clonal history of a cord blood donor cell leukemia with prenatal somatic JAK2 V617F mutation.

Author

Hirsch P, Mamez AC, Belhocine R, Lapusan S, Tang R, Suner L, Bories D, Marzac C, Fava F, Legrand O, Mohty M, Douay L, and Delhommeau F

Subjects
Allografts, Humans, Male, Middle Aged, Mutation, Tissue Donors, Cord Blood Stem Cell Transplantation adverse effects, Janus Kinase 2 genetics, Leukemia, Myeloid, Acute therapy, Neoplasms, Second Primary genetics
Published
2016
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21. Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia.

Author

Boutzen H, Saland E, Larrue C, de Toni F, Gales L, Castelli FA, Cathebas M, Zaghdoudi S, Stuani L, Kaoma T, Riscal R, Yang G, Hirsch P, David M, De Mas-Mansat V, Delabesse E, Vallar L, Delhommeau F, Jouanin I, Ouerfelli O, Le Cam L, Linares LK, Junot C, Portais JC, Vergez F, Récher C, and Sarry JE

Subjects
Amino Acid Substitution, Animals, Blast Crisis enzymology, Blast Crisis genetics, Blast Crisis pathology, CCAAT-Enhancer-Binding Proteins genetics, CCAAT-Enhancer-Binding Proteins metabolism, Cell Differentiation genetics, Cell Survival, Female, Granulocytes metabolism, Granulocytes pathology, HL-60 Cells, Humans, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute enzymology, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Male, Mice, Mice, Nude, Neoplasm Proteins genetics, Xenograft Model Antitumor Assays, Blast Crisis drug therapy, Cell Differentiation drug effects, Isocitrate Dehydrogenase metabolism, Leukemia, Myeloid, Acute drug therapy, Mutation, Missense, Neoplasm Proteins metabolism, Tretinoin pharmacology
Abstract

Acute myeloid leukemia (AML) is characterized by the accumulation of malignant blasts with impaired differentiation programs caused by recurrent mutations, such as the isocitrate dehydrogenase (IDH) mutations found in 15% of AML patients. These mutations result in the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG), leading to a hypermethylation phenotype that dysregulates hematopoietic differentiation. In this study, we identified mutant R132H IDH1-specific gene signatures regulated by key transcription factors, particularly CEBPα, involved in myeloid differentiation and retinoid responsiveness. We show that treatment with all-trans retinoic acid (ATRA) at clinically achievable doses markedly enhanced terminal granulocytic differentiation in AML cell lines, primary patient samples, and a xenograft mouse model carrying mutant IDH1. Moreover, treatment with a cell-permeable form of 2-HG sensitized wild-type IDH1 AML cells to ATRA-induced myeloid differentiation, whereas inhibition of 2-HG production significantly reduced ATRA effects in mutant IDH1 cells. ATRA treatment specifically decreased cell viability and induced apoptosis of mutant IDH1 blasts in vitro. ATRA also reduced tumor burden of mutant IDH1 AML cells xenografted in NOD-Scid-IL2rγ(null)mice and markedly increased overall survival, revealing a potent antileukemic effect of ATRA in the presence of IDH1 mutation. This therapeutic strategy holds promise for this AML patient subgroup in future clinical studies., (© 2016 Boutzen et al.)

Published
2016
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22. Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies.

Author

Saliba J, Saint-Martin C, Di Stefano A, Lenglet G, Marty C, Keren B, Pasquier F, Valle VD, Secardin L, Leroy G, Mahfoudhi E, Grosjean S, Droin N, Diop M, Dessen P, Charrier S, Palazzo A, Merlevede J, Meniane JC, Delaunay-Darivon C, Fuseau P, Isnard F, Casadevall N, Solary E, Debili N, Bernard OA, Raslova H, Najman A, Vainchenker W, Bellanné-Chantelot C, and Plo I

Subjects
Adolescent, Adult, Aged, Autophagy-Related Proteins, Child, Chromosomes, Human, Pair 14, Female, Humans, Induced Pluripotent Stem Cells cytology, Infant, Male, Pedigree, Phenotype, Young Adult, Gene Duplication, Genetic Predisposition to Disease, Germ Cells, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes genetics, Repressor Proteins genetics, Vesicular Transport Proteins genetics
Abstract

No major predisposition gene for familial myeloproliferative neoplasms (MPN) has been identified. Here we demonstrate that the autosomal dominant transmission of a 700-kb duplication in four genetically related families predisposes to myeloid malignancies, including MPN, frequently progressing to leukemia. Using induced pluripotent stem cells and primary cells, we demonstrate that overexpression of ATG2B and GSKIP enhances hematopoietic progenitor differentiation, including of megakaryocytes, by increasing progenitor sensitivity to thrombopoietin (TPO). ATG2B and GSKIP cooperate with acquired JAK2, MPL and CALR mutations during MPN development. Thus, the germline duplication may change the fitness of cells harboring signaling pathway mutations and increases the probability of disease development.

Published
2015
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23. Differential association of calreticulin type 1 and type 2 mutations with myelofibrosis and essential thrombocytemia: relevance for disease evolution.

Author

Cabagnols X, Defour JP, Ugo V, Ianotto JC, Mossuz P, Mondet J, Girodon F, Alexandre JH, Mansier O, Viallard JF, Lippert E, Murati A, Mozziconacci MJ, Saussoy P, Vekemans MC, Knoops L, Pasquier F, Ribrag V, Solary E, Plo I, Constantinescu SN, Casadevall N, Vainchenker W, Marzac C, and Bluteau O

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Child, Female, Humans, Male, Middle Aged, Young Adult, Calreticulin genetics, Mutation, Primary Myelofibrosis genetics, Protein Isoforms genetics, Thrombocythemia, Essential genetics
Published
2015
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24. Prognosis of body mass index and chemotherapy dose capping in acute myeloid leukaemia.

Author

Kempf E, Hirsch P, Labopin M, Viguié F, Isnard F, Tang R, Marzac C, Marie JP, Mohty M, and Legrand O

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Prognosis, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Body Mass Index, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy
Abstract

Body Mass Index (BMI) prognosis in acute myeloid leukaemia (AML) is unknown. Capping chemotherapy dose at 2m(2) of body surface area (BSA) is used without any rationale. We assessed whether both of them could be correlated with outcome in 233 AML patients. Thirty three percent were overweight, 10% obese and BSA over 2m(2) was observed in 15%. BMI and BSA>2m(2) were not associated with OS (p=0.16; p=0.39), nor with DFS (p=0.18; p=0.42), nor with CR. OS-associated factors were age (p<0.001), cytogenetic (p=0.002), FLT3-ITD (p=0.01). BMI and chemotherapy dose capping are not pejorative factors on intensively treated AML patients., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Published
2014
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25. Interest of cytogenetic and FISH evaluation for prognosis evaluation in 198 patients with acute myeloid leukemia in first complete remission in a single institution.

Author

Hirsch P, Labopin M, Viguié F, Perot C, Isnard F, Mamez AC, Bilhou-Nabera C, Marzac C, Delhommeau F, Lapusan S, Marie JP, Mohty M, and Legrand O

Subjects
Abnormal Karyotype, Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, In Situ Hybridization, Fluorescence, Leukemia, Myeloid, Acute genetics, Male, Middle Aged, Neoplasm, Residual, Predictive Value of Tests, Prognosis, Remission Induction, Young Adult, Cytogenetic Analysis methods, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute therapy
Abstract

The prognostic interest of cytogenetic remission and fluorescent in situ hybridization (FISH) evaluation in patients with abnormal karyotype acute myeloid leukemia (AML) has been poorly studied. Among 198 patients that reached complete remission (CR), 24 did not reach cytogenetic remission (CyCR). CyCR had no prognosis impact, especially in patients with intermediate or unfavorable cytogenetic. Twenty of 52 evaluated patients in CyCR did not reach FISH CR. FISH CR was associated with better OS (p=0.004) and tended to be associated with better disease-free survival (DFS) (p=0.08). FISH evaluation may be a useful tool for prognosis evaluation and minimal residual disease (MRD) assessment in patients with abnormal cytogenetic AML., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Published
2014
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26. JAK2V617F mRNA metabolism in myeloproliferative neoplasm cell lines.

Author

Nauroy P, Delhommeau F, and Baklouti F

Subjects
Cell Line, Tumor, Haplotypes, Humans, Mutation, Myeloproliferative Disorders pathology, RNA Splicing, RNA, Messenger genetics, Janus Kinase 2 genetics, Myeloproliferative Disorders genetics, Myeloproliferative Disorders metabolism, RNA, Messenger metabolism
Published
2014
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27. A web-based delphi study for eliciting helpful criteria in the positive diagnosis of hemophagocytic syndrome in adult patients.

Author

Hejblum G, Lambotte O, Galicier L, Coppo P, Marzac C, Aumont C, and Fardet L

Subjects
Adult, Consensus, Delphi Technique, Humans, Internet, Surveys and Questionnaires, Lymphohistiocytosis, Hemophagocytic diagnosis
Abstract

The diagnosis of the reactive form of hemophagocytic syndrome in adults remains particularly difficult since none of the clinical or laboratory manifestations are specific. We undertook a study in order to elicit which features constitute helpful criteria for a positive diagnosis. In this Delphi study, the features investigated in the questionnaire and the experts invited to participate in the survey were issued from a bibliographic search. The questionnaire was iteratively proposed to experts via a web-based application with a feedback of the results observed at the preceding Delphi round. Experts were asked to label each investigated criterion in one of the following categories: absolutely required, important, of minor interest, or not assessable in the routine practice environment. A positive consensus was a priori defined as at least 75% answers observed in the categories absolutely required and important. The questionnaire investigated 26 criteria and 24 experts originating from 13 countries participated in the second and final Delphi round. A positive consensus was reached for the nine following criteria: unilineage cytopenia, bicytopenia, pancytopenia, presence of hemophagocytosis pictures on a bone marrow aspirate or on a tissue biopsy, high ferritin level, fever, organomegaly, presence of a predisposing underlying disease, and high level of lactate dehydrogenase. A negative consensus was reached for 13 criteria, and an absence of consensus was observed for 4 criteria. The study constitutes the first initiative to date for defining international guidelines devoted to the positive diagnosis of the reactive form of hemophagocytic syndrome.

Published
2014
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