title: Chromatin redistribution of the DEK oncoprotein represses hTERT transcription in leukemias.
abstract: Although numerous factors have been found to modulate hTERT transcription, the mechanism of its repression in certain leukemias remains unknown. We show here that DEK represses hTERT transcription through its enrichment on the hTERT promoter in cells from chronic and acute myeloid leukemias, chronic lymphocytic leukemia, but not acute lymphocytic leukemias where hTERT is overexpressed. We isolated DEK from the hTERT promoter incubated with nuclear extracts derived from fresh acute myelogenous leukemia (AML) cells and from cells expressing Tax, an hTERT repressor encoded by the human T cell leukemia virus type 1. In addition to the recruitment of DEK, the displacement of two potent known hTERT transactivators from the hTERT promoter characterized both AML cells and Tax-expressing cells. Reporter and chromatin immunoprecipitation assays permitted to map the region that supports the repressive effect of DEK on hTERT transcription, which was proportionate to the level of DEK-promoter association but not with the level of DEK expression. Besides hTERT repression, this context of chromatin redistribution of DEK was found to govern about 40% of overall transcriptional modifications, including those of cancer-prone genes. In conclusion, DEK emerges as an hTERT repressor shared by various leukemia subtypes and seems involved in the deregulation of numerous genes associated with leukemogenesis.
authors.affiliation: Université de Lyon 1, Centre National pour la Recherche Scientifique UMR5239, Oncovirologie et Biothérapies, Centre Léon Bérard, Lyon Cedex, France.
authors.forename: Maroun
authors.initials: M
authors.lastname: Karam
authors.affiliation: Université de Lyon 1, Centre National pour la Recherche Scientifique UMR5239, Oncovirologie et Biothérapies, Centre Léon Bérard, Lyon Cedex, France.
authors.forename: Morgan
authors.initials: M
authors.lastname: Thenoz
authors.affiliation: Université de Lyon 1, Centre National pour la Recherche Scientifique UMR5239, Oncovirologie et Biothérapies, Centre Léon Bérard, Lyon Cedex, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Capraro
authors.affiliation: Université de Lyon 1, Centre National pour la Recherche Scientifique UMR5239, Oncovirologie et Biothérapies, Centre Léon Bérard, Lyon Cedex, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Robin
authors.affiliation: Université de Lyon 1, Centre National pour la Recherche Scientifique UMR5239, Oncovirologie et Biothérapies, Centre Léon Bérard, Lyon Cedex, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Pinatel
authors.affiliation: Université de Lyon 1, Centre National pour la Recherche Scientifique UMR5239, Oncovirologie et Biothérapies, Centre Léon Bérard, Lyon Cedex, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Lancon
authors.affiliation: Université de Lyon 1, Centre National pour la Recherche Scientifique UMR5239, Oncovirologie et Biothérapies, Centre Léon Bérard, Lyon Cedex, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Galia
authors.affiliation: Université de Lyon 1, Centre National pour la Recherche Scientifique UMR5239, Oncovirologie et Biothérapies, Centre Léon Bérard, Lyon Cedex, France ; Service d'Hématologie Adultes, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Sibon
authors.affiliation: Service d'Hématologie, Pavillon Marcel Bérard, Centre Hospitalier Lyon-Sud 165, Pierre Bénite Cedex, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Thomas
authors.affiliation: Service d'Hématologie, Pavillon Marcel Bérard, Centre Hospitalier Lyon-Sud 165, Pierre Bénite Cedex, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Ducastelle-Lepretre
authors.affiliation: Service d'Hématologie, Pavillon Marcel Bérard, Centre Hospitalier Lyon-Sud 165, Pierre Bénite Cedex, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Nicolini
authors.affiliation: Service d'Hématologie, Pavillon Marcel Bérard, Centre Hospitalier Lyon-Sud 165, Pierre Bénite Cedex, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Hamri
authors.affiliation: Service d'Hématologie, Pavillon Marcel Bérard, Centre Hospitalier Lyon-Sud 165, Pierre Bénite Cedex, France.
authors.forename: Youcef
authors.initials: Y
authors.lastname: Chelghoun
authors.affiliation: Université de Lyon 1, Centre National pour la Recherche Scientifique UMR5239, Oncovirologie et Biothérapies, Centre Léon Bérard, Lyon Cedex, France ; Service d'Hématologie, Pavillon Marcel Bérard, Centre Hospitalier Lyon-Sud 165, Pierre Bénite Cedex, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Wattel
authors.affiliation: Université de Lyon 1, Centre National pour la Recherche Scientifique UMR5239, Oncovirologie et Biothérapies, Centre Léon Bérard, Lyon Cedex, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Mortreux
mesh_terms: D001854:Bone Marrow Cells / Q000166:cytology; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D016356:Gene Products, tax / Q000378:metabolism; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D009693:Nucleic Acid Hybridization; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism*
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; C084738:DEK protein, human; D016356:Gene Products, tax; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; C509186:TERT protein, human; D019098:Telomerase