Human erythroleukemia genetics and transcriptomes identify master transcription factors as functional disease drivers.

Autor:	Fagnan A; Unité 1170 (U1170), INSERM, Gustave Roussy, Université Paris Diderot, Villejuif, France.; Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France., Bagger FO; University Children's Hospital Beider Basel (UKBB), Basel, Switzerland.; Department of Biomedicine, University of Basel, Basel, Switzerland.; Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark.; Swiss Institute of Bioinformatics, Basel, Basel, Switzerland., Piqué-Borràs MR; University Children's Hospital Beider Basel (UKBB), Basel, Switzerland.; Department of Biomedicine, University of Basel, Basel, Switzerland., Ignacimouttou C; Unité 1170 (U1170), INSERM, Gustave Roussy, Université Paris Diderot, Villejuif, France.; Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France., Caulier A; Equipe d'Accueil (EA) 4666, Hématopoïèse et Immunologie (HEMATIM), Université de Picardie Jules Verne (UPJV), Amiens, France.; Service Hématologie Biologique, Centre Hospitalier Universitaire (CHU) Amiens, Amiens, France., Lopez CK; Unité 1170 (U1170), INSERM, Gustave Roussy, Université Paris Diderot, Villejuif, France.; Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France., Robert E; Unité 1170 (U1170), INSERM, Gustave Roussy, Université Paris Diderot, Villejuif, France.; Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France., Uzan B; Unité Mixte de Recherche 967 (UMR 967), INSERM-Commissariat à l'Énergie Atomique et aux Énergies Alternatives (CEA)/Direction de la Recherche Fondamentale (DRF)/Institut de Biologie François Jacob (IBFJ)/Institut de Radiobiologie Cellulaire et Moléculaire (IRCM)/Laboratoire des cellules Souches Hématopoïétiques et des Leucémies (LSHL)-Université Paris-Diderot-Université Paris-Sud, Fontenay-aux-Roses, France., Gelsi-Boyer V; U1068 and.; UMR7258, Centre de Recherche en Cancérologie de Marseille, Centre National de la Recherche Scientifique (CNRS)/INSERM/Institut Paoli Calmettes/Aix-Marseille Université, Marseille, France., Aid Z; Unité 1170 (U1170), INSERM, Gustave Roussy, Université Paris Diderot, Villejuif, France.; Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France., Thirant C; Unité 1170 (U1170), INSERM, Gustave Roussy, Université Paris Diderot, Villejuif, France.; Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France., Moll U; Institute of Molecular Oncology, University Medical Center Göttingen, Göttingen, Germany.; Department of Pathology, Stony Brook University, Stony Brook, NY., Tauchmann S; University Children's Hospital Beider Basel (UKBB), Basel, Switzerland.; Department of Biomedicine, University of Basel, Basel, Switzerland., Kurtovic-Kozaric A; Clinical Center of the University of Sarajevo, University of Sarajevo, Sarajevo, Bosnia and Herzegovina., Maciejewski J; Department of Translational Hematology and Oncologic Research, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH., Dierks C; Hämatologie, Onkologie und Stammzelltransplantation, Klinik für Innere Medizin I, Freiburg, Germany., Spinelli O; UOC Ematologia, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII Hospital, Bergamo, Italy., Salmoiraghi S; UOC Ematologia, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII Hospital, Bergamo, Italy.; FROM Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy., Pabst T; Department of Oncology, Inselspital, University Hospital Bern/University of Bern, Bern, Switzerland., Shimoda K; Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan., Deleuze V; IGMM, University of Montpellier, CNRS, Montpellier, France.; Université de Paris, Laboratory of Excellence GR-Ex, Paris, France., Lapillonne H; Centre de Recherche Saint Antoine (CRSA)-Unité INSERM, Sorbonne Université/Assistance Publique-Hôpitaux de Paris (AP-HP)/Hôpital Trousseau, Paris, France., Sweeney C; Medical Research Council Molecular Haematology Unit (MRC MHU), Biomedical Research Centre (BRC) Hematology Theme, Oxford Biomedical Research Centre, Oxford Centre for Haematology, Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom., De Mas V; Team 16, Hematology Laboratory, Center of Research of Cancerology of Toulouse, U1037, INSERM/Institut Universitaire du Cancer de Toulouse (IUCT) Oncopole, Toulouse, France., Leite B; Genomic Platform, Unité Mixte de Service - Analyse Moléculaire, Modélisation et Imagerie de la maladie Cancéreuse (UMS AMMICA), Gustave Roussy/Université Paris-Saclay, Villejuif, France., Kadri Z; Division of Innovative Therapies, UMR-1184, Immunologie des Maladies Virales, Auto-immunes, Hématologiques et Bactériennes (IMVA-HB) and Infectious Disease Models and Innovative Therapies (IDMIT) Center, CEA/INSERM/Paris-Saclay University, Fontenay-aux-Roses, France., Malinge S; Unité 1170 (U1170), INSERM, Gustave Roussy, Université Paris Diderot, Villejuif, France.; Telethon Kids Institute, Perth Children's Hospital, Nedlands, WA, Australia., de Botton S; Unité 1170 (U1170), INSERM, Gustave Roussy, Université Paris Diderot, Villejuif, France.; Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France., Micol JB; Unité 1170 (U1170), INSERM, Gustave Roussy, Université Paris Diderot, Villejuif, France., Kile B; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia., Carmichael CL; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia., Iacobucci I; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN., Mullighan CG; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN.; Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN., Carroll M; Division of Hematology and Oncology, University of Pennsylvania, PA., Valent P; Division of Hematology and Hemostaseology, Department of Internal Medicine I and.; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria., Bernard OA; Unité 1170 (U1170), INSERM, Gustave Roussy, Université Paris Diderot, Villejuif, France.; Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France., Delabesse E; Team 16, Hematology Laboratory, Center of Research of Cancerology of Toulouse, U1037, INSERM/Institut Universitaire du Cancer de Toulouse (IUCT) Oncopole, Toulouse, France., Vyas P; Medical Research Council Molecular Haematology Unit (MRC MHU), Biomedical Research Centre (BRC) Hematology Theme, Oxford Biomedical Research Centre, Oxford Centre for Haematology, Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom., Birnbaum D; U1068 and.; UMR7258, Centre de Recherche en Cancérologie de Marseille, Centre National de la Recherche Scientifique (CNRS)/INSERM/Institut Paoli Calmettes/Aix-Marseille Université, Marseille, France., Anguita E; Hematology Department.; Instituto de Medicina de Laboratorio (IML), and.; Instituto de Investigación Sanitaria San Carlos, (IdISSC), Hospital Clínico San Carlos (HCSC), Madrid, Spain; and.; Department of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain., Garçon L; Equipe d'Accueil (EA) 4666, Hématopoïèse et Immunologie (HEMATIM), Université de Picardie Jules Verne (UPJV), Amiens, France.; Service Hématologie Biologique, Centre Hospitalier Universitaire (CHU) Amiens, Amiens, France., Soler E; IGMM, University of Montpellier, CNRS, Montpellier, France.; Université de Paris, Laboratory of Excellence GR-Ex, Paris, France., Schwaller J; University Children's Hospital Beider Basel (UKBB), Basel, Switzerland.; Department of Biomedicine, University of Basel, Basel, Switzerland., Mercher T; Unité 1170 (U1170), INSERM, Gustave Roussy, Université Paris Diderot, Villejuif, France.; Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2020 Aug 06; Vol. 136 (6), pp. 698-714.
DOI:	10.1182/blood.2019003062
Abstrakt:	Acute erythroleukemia (AEL or acute myeloid leukemia [AML]-M6) is a rare but aggressive hematologic malignancy. Previous studies showed that AEL leukemic cells often carry complex karyotypes and mutations in known AML-associated oncogenes. To better define the underlying molecular mechanisms driving the erythroid phenotype, we studied a series of 33 AEL samples representing 3 genetic AEL subgroups including TP53-mutated, epigenetic regulator-mutated (eg, DNMT3A, TET2, or IDH2), and undefined cases with low mutational burden. We established an erythroid vs myeloid transcriptome-based space in which, independently of the molecular subgroup, the majority of the AEL samples exhibited a unique mapping different from both non-M6 AML and myelodysplastic syndrome samples. Notably, >25% of AEL patients, including in the genetically undefined subgroup, showed aberrant expression of key transcriptional regulators, including SKI, ERG, and ETO2. Ectopic expression of these factors in murine erythroid progenitors blocked in vitro erythroid differentiation and led to immortalization associated with decreased chromatin accessibility at GATA1-binding sites and functional interference with GATA1 activity. In vivo models showed development of lethal erythroid, mixed erythroid/myeloid, or other malignancies depending on the cell population in which AEL-associated alterations were expressed. Collectively, our data indicate that AEL is a molecularly heterogeneous disease with an erythroid identity that results in part from the aberrant activity of key erythroid transcription factors in hematopoietic stem or progenitor cells. (© 2020 by The American Society of Hematology.)
Databáze:	MEDLINE
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