Myeloid Translocation Gene 16 (MTG16) Regulates Lymphopoiesis

The Myeloid Translocation Gene (MTG) family was first discovered through the (8;21) translocation that leads to acute myeloid leukemia. This translocation fuses nearly all of Myeloid Translocation Gene 8 (MTG8) to an N-terminal portion of Acute Myeloid Leukemia 1 (AML1), thus disrupting the normal function of MTG8 as a transcriptional co-repressor. Two other family members have since been identified: Myeloid Translocation Gene 16 (MTG16) and Myeloid Tumor Gene Related-1 (MTGR1), both of which are implicated in leukemogenesis. To examine the physiological roles of Mtg16, a target of the t(16;21) that produces Acute Myeloid Leukemia, we deleted it in mice. We found that deletion of Mtg16 perturbs both B-and T-cell development, resulting in a reduced number of peripheral lymphocytes confirmed by complete blood counts and flow cytometry analysis of spleen and lymph node populations. These mice also display a dramatic two-to-three fold decrease in thymic cellularity. Analysis of the bone marrow indicated that there was also loss of B220+ cells, suggesting that there was a general deficit in lymphopoiesis in the absence of Mtg16. Upon closer examination, we find several significant changes throughout the development of both B and T cells. B-cells accumulate in the earliest stages of development, with Pre-pro B increasing in proportion of total B cells after inactivation of Mtg16. This change occurs at the expense of more mature populations, as immature and mature B-cells decrease in percentage significantly. Mtg16 (−/−) thymocytes show slight but statistically significant decreases in Double Negative 1 (DN1) and Double Negative 2 (DN2) subpopulations. Thymocytes also accumulate in the most mature CD4+ and CD8+ subsets in the absence of Mtg16. Mtg16 thus regulates lymphopoiesis at multiple steps, but the most intriguing changes occur in stem and progenitor populations. In fact, the deletion of Mtg16 also results in an increase in myeloid lineages, particularly granulocytes and macrophages, suggesting that Mtg16 plays a role in myeloid vs. lymphoid lineage decisions. Indeed, the deficit in lymphopoiesis appears to be due to increased myeloid commitment and/or expansion of myeloid progenitor cells. Even when cultured in conditions favoring lymphopoiesis, Mtg16-null lineage-/Sca1+/c-Kit+ cells displayed a predisposition towards myeloid development. Because of its ability to interact with a number of different transcription factors that participate in lymphoid and myeloid cell fate decisions, Mtg16 may provide a key piece of the transcriptional machinery that regulates lineage commitment.

Myeloid Translocation Gene Family Members Associate with T-Cell Factors (TCFs) and Influence TCF-Dependent Transcription

ABSTRACT Canonical Wnt signaling is mediated by a molecular “switch” that regulates the transcriptional properties of the T-cell factor (TCF) family of DNA-binding proteins. Members of the myeloid translocation gene (MTG) family of transcriptional corepressors are frequently disrupted by chromosomal translocations in acute myeloid leukemia, whereas MTG16 may be inactivated in up to 40% of breast cancer and MTG8 is a candidate cancer gene in colorectal carcinoma. Genetic studies imply that this corepressor family may function in stem cells. Given that mice lacking Myeloid Translocation Gene Related-1 (Mtgr1) fail to maintain the secretory lineage in the small intestine, we surveyed transcription factors that might recruit Mtgr1 in intestinal stem cells or progenitor cells and found that MTG family members associate specifically with TCF4. Coexpression of β-catenin disrupted the association between these corepressors and TCF4. Furthermore, when expressed in Xenopus embryos, MTG family members inhibited axis formation and impaired the ability of β-catenin and XLef-1 to induce axis duplication, indicating that MTG family members act downstream of β-catenin. Moreover, we found that c-Myc, a transcriptional target of the Wnt pathway, was overexpressed in the small intestines of mice lacking Mtgr1, thus linking inactivation of Mtgr1 to the activation of a potent oncogene.