Transcription intermediary factor 1? is a tumor suppressor in mouse and human chronic myelomonocytic leukemia.

ABSTRACT: Transcription intermediary factor 1? (TIF1?) was suggested to play a role in erythropoiesis. However, how TIF1? regulates the development of different blood cell lineages and whether TIF1? is involved in human hematological malignancies remain to be determined. Here we have shown that TIF1? 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. TIF1? 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 TIF1? expression. Together, these results demonstrate that TIF1G is an epigenetically regulated tumor suppressor gene in hematopoietic cells and suggest that changes in TIF1? expression may be a biomarker of response to demethylating agents in CMML.

SUBMITTER: Aucagne R 

PROVIDER: S-EPMC3104753 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature