title: Transcription intermediary factor 1γ is a tumor suppressor in mouse and human chronic myelomonocytic leukemia.
abstract: Transcription intermediary factor 1γ (TIF1γ) was suggested to play a role in erythropoiesis. However, how TIF1γ regulates the development of different blood cell lineages and whether TIF1γ is involved in human hematological malignancies remain to be determined. Here we have shown that TIF1γ was a tumor suppressor in mouse and human chronic myelomonocytic leukemia (CMML). Loss of Tif1g in mouse HSCs favored the expansion of the granulo-monocytic progenitor compartment. Furthermore, Tif1g deletion induced the age-dependent appearance of a cell-autonomous myeloproliferative disorder in mice that recapitulated essential characteristics of human CMML. TIF1γ was almost undetectable in leukemic cells of 35% of CMML patients. This downregulation was related to the hypermethylation of CpG sequences and specific histone modifications in the gene promoter. A demethylating agent restored the normal epigenetic status of the TIF1G promoter in human cells, which correlated with a reestablishment of TIF1γ expression. Together, these results demonstrate that TIF1G is an epigenetically regulated tumor suppressor gene in hematopoietic cells and suggest that changes in TIF1γ expression may be a biomarker of response to demethylating agents in CMML.
authors.affiliation: Inserm UMR 866, University of Burgundy, Dijon, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Aucagne
authors.forename: Nathalie
authors.initials: N
authors.lastname: Droin
authors.forename: Jérôme
authors.initials: J
authors.lastname: Paggetti
authors.forename: Brice
authors.initials: B
authors.lastname: Lagrange
authors.forename: Anne
authors.initials: A
authors.lastname: Largeot
authors.forename: Arlette
authors.initials: A
authors.lastname: Hammann
authors.forename: Amandine
authors.initials: A
authors.lastname: Bataille
authors.forename: Laurent
authors.initials: L
authors.lastname: Martin
authors.forename: Kai-Ping
authors.initials: KP
authors.lastname: Yan
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.forename: Régine
authors.initials: R
authors.lastname: Losson
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.forename: Jean-Noël
authors.initials: JN
authors.lastname: Bastie
authors.forename: Laurent
authors.initials: L
authors.lastname: Delva
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D001483:Base Sequence; D002454:Cell Differentiation; D019175:DNA Methylation; D000077209:Decitabine; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D016147:Genes, Tumor Suppressor; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics; D013047:Specific Pathogen-Free Organisms; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D000964:Antimetabolites, Antineoplastic; D009363:Neoplasm Proteins; C511956:TRIM33 protein, human; D014157:Transcription Factors; C491420:Trim33 protein, mouse; D000077209:Decitabine; D016186:Receptor, Macrophage Colony-Stimulating Factor; D001374:Azacitidine