Two members of the MTG/ETO family of transcriptional corepressors, MTG8 and MTG16, are disrupted by chromosomal translocations in up to 15% of acute myeloid leukemia cases. The third family member, MTGR1, was identified as a factor that associates with the t(8;21) fusion protein RUNX1-MTG8. We demonstrate that Mtgr1 associates with mSin3A, N-CoR, and histone deacetylase 3 and that when tethered to DNA, Mtgr1 represses transcription, suggesting that Mtgr1 also acts as a transcriptional corepressor. To define the biological function of Mtgr1, we created Mtgr1-null mice. These mice are proportionally smaller than their littermates during embryogenesis and throughout their life span but otherwise develop normally. However, these mice display a progressive reduction in the secretory epithelial cell lineage in the small intestine. This is not due to the loss of small intestinal progenitor cells expressing Gfi1, which is required for the formation of goblet and Paneth cells, implying that loss of Mtgr1 impairs the maturation of secretory cells in the small intestine.Chromosomal translocations disrupt master regulatory genes that control cellular proliferation, apoptosis, and the lineage decisions that affect stem cell self-renewal and differentiation of progenitor cells (15,29). The myeloid translocation gene on chromosome 8 (MTG8, also known as eighttwenty-one or ETO) is disrupted by t(8;21) in up to 15% of acute myeloid leukemia cases (7,26,27). MTG8 is the founding member of a gene family that includes the myeloid translocation gene on chromosome 16 (MTG16 or ETO2), which is disrupted by t(16;21), and myeloid translocation gene-related 1 (MTGR1) (5, 6, 12, 18). t(8;21) and t(16;21) fuse MTG8 and MTG16, respectively, to the DNA binding domain of Runtrelated 1 (RUNX1, also known as acute myeloid leukemia 1 or AML1) (7,12,26,27). The resulting fusion proteins repress RUNX1-regulated genes (11,20,25). For RUNX1-MTG8, this repression requires the MTG8 sequences, leading to the hypothesis that MTG8 is a transcriptional corepressor (20). Consistent with this hypothesis, MTG8 associates with multiple corepressors, including N-CoR/SMRT, mSin3, and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3 (1,13,14,23,34).MTG family members display approximately 85% sequence similarity (3) and contain four conserved subdomains with up to 95% identity (5, 8). Based on homology to MTG8, it was anticipated that MTG16 and MTGR1 also act as transcriptional corepressors. MTG16 is 92% homologous to MTG8, and the murine form of MTG16, Eto2, interacts with multiple HDACs and N-CoR (1). In contrast to MTG8, Eto2 failed to interact with mSin3A (1). The MTG family members also heterodimerize, and this property allowed the identification of MTGR1 as a RUNX1-MTG8-associated protein (18). Although it associates with MTG8 and the t(8;21) fusion protein, the molecular function of MTGR1 is unknown.While two of the three MTG family members are disrupted by chromosomal translocations, the MTG family members are widely expressed, suggesting that this gene f...

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