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 agedependent 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.

Molecular similarity between myelodysplastic form of chronic myelomonocytic leukemia and refractory anemia with ring sideroblasts

“…31 Splicing defects in SRSF2 in CMML and in SF3B1 in RARS may affect genes involved in erythropoiesis such as ABCB7, FTL, GATA1, or HAMP for example, or a master transcription factor of hematopoietic cell lineages such as TIF1γ, which controls erythroid cell fate and acts as a tumor suppressor in CMML. [43][44][45] However, SRSF2 mutations are also found in MP-CMML which does not show a red cell program. MP-CMML is characterized by mutations in signaling genes, and this could modify the effect of SRSF2.…”

Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β–dependent mechanisms

“…TRIM33 and its relatives are chromatin-associated transcriptional repressors characterized by an N-terminal RING domain and a C-terminal PHD (plant homeodomain)-bromodomain cassette that interacts with posttranslationally modified histone tails. TRIM33 has been characterized as a key factor controlling cell fate decisions during embryonic development (19,20) and is an established tumor suppressor in pancreatic cancer, hepatocellular carcinoma, and chronic myelomonocytic leukemia (21)(22)(23). Roles of TRIM33 in development and as a tumor suppressor have been attributed to its ability to strongly modulate TGF-β signaling through interactions with SMAD family transcription factors (24,25).…”

Myelodysplastic/Myeloproliferative Neoplasms

“…In a recent study, Delva et al 22 have shown that, in mice, tissue-targeted deletion of the gene encoding transcription intermediary factor 1␥ (Tif1␥) leads to development of a CMML-like myeloproliferative disease with monocytic features. Interestingly, the human TIF1G gene expression was almost undetectable in sorted leukemic cells of ϳ35% of patients with CMML, and this decreased expression was related to the hypermethylation of CpG islands and a specific pattern of histone modifications on the gene promoter.…”