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RESEARCH PRODUCT
Transcription intermediary factor 1γ is a tumor suppressor in mouse and human chronic myelomonocytic leukemia.
Nathalie DroinAnne LargeotEric SolaryJérôme PaggettiJean-noël BastieArlette HammannKai-ping YanRomain AucagneAmandine BatailleLaurent DelvaPierre FenauxBrice LagrangeRégine LossonLaurent Martinsubject
MaleAgingAntimetabolites AntineoplasticTumor suppressor geneCellular differentiationMolecular Sequence DataChronic myelomonocytic leukemiaReceptor Macrophage Colony-Stimulating FactorBiologyDecitabinechemistry.chemical_compoundMicemedicineAnimalsHumansGenes Tumor SuppressorPromoter Regions GeneticTranscription factorAgedAged 80 and overMice KnockoutBase SequenceGene Expression Regulation LeukemicCell DifferentiationLeukemia Myelomonocytic ChronicGeneral MedicineDNA MethylationMiddle Agedmedicine.diseaseTRIM33Hematopoietic Stem CellsMolecular biologyDemethylating agentHematopoiesisNeoplasm ProteinsSpecific Pathogen-Free OrganismsHaematopoiesischemistryDNA methylationCancer researchAzacitidineFemaleTranscription FactorsResearch Articledescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2011-06-01 | The Journal of clinical investigation |