MTG16, a target of the t(16;21), contributes to murine lymphoid development

Abstract

The Myeloid Translocation Gene (MTG) family was first discovered through the (8;21) translocation that leads to acute myeloid leukemia by fusing nearly all of Myeloid Translocation Gene 8 (MTG8) to an N-terminal portion of Acute Myeloid Leukemia 1 (AML1) and redirecting the normal function of MTG8 as a transcriptional co-repressor. The two other family members, Myeloid Translocation Gene 16 (MTG16) and Myeloid Tumor Gene Related-1 (MTGR1), are also implicated in leukemogenesis and function by forming corepressor complexes with proteins such as Nuclear Receptor Corepressor 1 (N-CoR) and histone deacetylases, recruiting them to transcription factor binding partners to regulate gene expression. To examine the physiological roles of Mtg16, we created a knock-out mouse model and found that deletion of Mtg16 perturbs hematopoietic stem cell function and affects both T and B-cell development, resulting in a reduced number of both developing thymocytes and mature B and T cells. Thorough characterization of the in vivo development of B and T cells found several changes throughout the development of both populations with the most significant changes in the stem, progenitor, and early lineage committed compartments. These changes are exacerbated after stress: both B and T cell development are nearly eliminated after bone marrow transplant and in vitro differentiation assays show striking deficits. While the defects to B and T cell development show similarity, mechanistic differences have become apparent. The defect in Mtg16(-/-) in vitro T cell development can be complimented with retroviral reintroduction of Mtg16 and we identified interactions with both the Notch Intracellular Domain and E2A as critical to the function of Mtg16 in specifying T-cell fate. The deficit in in vitro B-cell development in the absence of Mtg16 appears to be a growth deficit, and we have data to suggest that removal of p53 can overcome this deficit and restore in vitro growth. We hypothesize that through interactions with different transcription factors, Mtg16 regulates lymphoid lineage commitment, growth, and survival.