Emerging Roles of MTG16 in Cell-Fate Control of Hematopoietic Stem Cells and Cancer

Abstract

MTG16 (myeloid translocation gene on chromosome 16) and its related proteins, MTG8 and MTGR1, define a small family of transcriptional corepressors. These corepressors share highly conserved domain structures yet have distinct biological functions and tissue specificity. In vivo studies have shown that, of the three MTG corepressors, MTG16 is uniquely important for the regulation of hematopoietic stem/progenitor cell (HSPC) proliferation and differentiation. Apart from this physiological function, MTG16 is also involved in carcinomas and leukemias, acting as the genetic target of loss of heterozygosity (LOH) aberrations in breast cancer and recurrent translocations in leukemia. The frequent involvement of MTG16 in these disease etiologies implies an important developmental role for this transcriptional corepressor. Furthermore, mounting evidence suggests that MTG16 indirectly alters the disease course of several leukemias via its regulatory interactions with a variety of pathologic fusion proteins. For example, a recent study has shown that MTG16 can repress not only wild-type E2A-mediated transcription, but also leukemia fusion protein E2A-Pbx1-mediated transcription, suggesting that MTG16 may serve as a potential therapeutic target in acute lymphoblastic leukemia expressing the E2A-Pbx1 fusion protein. Given that leukemia stem cells share similar regulatory pathways with normal HSPCs, studies to further understand how MTG16 regulates cell proliferation and differentiation could lead to novel therapeutic approaches for leukemia treatment.

The Pluripotency Regulator PRDM14 Requires Hematopoietic Regulator CBFA2T3 to Initiate Leukemia in Mice

“…However, specificity arises because they are normally expressed in different cell types. Consistently, CBFA2T3 expression is high in hematopoietic stem and progenitor cells, and decreases during differentiation, remaining high in megakaryocyte-erythroid and B220 þ progenitor cells (27,28). In mouse HSCs, Cbfa2t3 is expressed at twice the level of Cbfa2t2 (36), which could give CBFA2T3 a competitive advantage over CBFA2T2 for interaction with PRDM14.…”

“…PRDM14 binds DNA at a specific sequence that is identical between mouse and human (GGTC[TC]CTAA) through its six zinc fingers (7,8). ETO family members do not bind DNA directly, so it is likely that PRDM14 serves as a bridge between DNA and CBFA2T3, while the NHR3 and NHR4 domains complex with other chromatin-modifying proteins (27), similar to other related family members that contain Nervy homology domains (Fig. 6).…”

“…6). CBFA2T3 may form a corepressor complex with histone deacetylases (HDAC) 1-3 as well as 6 and 8 to regulate gene expression in this context as well (18,27). Thus, PRDM14 may recruit repressive CBFA2T3 and indirectly HDAC proteins that are capable of depositing epigenetic marks onto chromatin at specific DNA targets.…”

“…CBFA2T3 contains four NHR domains that bind diverse types of proteins, enabling it to act as a bridge between transcription factors that bind NHR1 and chromatin-modi-fying enzymes that bind NHR3-4 (27). PRDM14 interacts with other proteins primarily via its PR domain (17).…”

“…Together, these data demonstrate that PRDM14 and CBFA2T3 interact through the PR and NHR1 domains, respectively. Altering levels of Cbfa2t3 can prevent or slow T-ALL development Cbfa2t3 is important for HSC self-renewal and is most highly expressed in hematopoietic stem and progenitor cells (27)(28)(29)(30). Therefore, we hypothesized that a misappropriation of its role in BM when PRDM14 is ectopically present is critical for T-ALL pathogenesis.…”