Mtg16 NHR1 mutations cause defects in lymphopoiesis and the response to anemia.

Abstract

The eight-twenty-one (ETO)/myeloid translocation gene (MTG) family of transcriptional corepressors play a key role in adult stem cell function across multiple tissues and may be affected by mutation, deletion, or translocation in solid tumors and leukemia. Structural studies of the first conserved domain identified residues that make specific contacts with E proteins, such as HEB and E2A. We generated mice with a mutation in a critical phenylalanine (F210A) in Mtg16 to test the physiological significance of Mtg16 association with E proteins and compared these mice to mice containing a nearby cancer-associated mutation (P209T). We found that Mtg16^-/- and Mtg16^F210A/F210A mice showed impaired lymphopoiesis following competitive bone marrow transplant, suggesting that the repression of E protein-dependent transcription is critical for B- and T-cell development. Although Mtg16^-/-, Mtg16^P209T/P209T, and Mtg16^F210A/F210A animals showed significant defects in burst forming potential (BFU-E) after phenylhydrazine treatment, only Mtg16^-/- mice showed overt signs of anemia. Thus, we propose that, although Mtg16 is a critical regulator of human pluripotent stem cell (HSPC) function, response to hemolytic anemia, and lymphoid development, the interaction between Mtg16 and E proteins is particularly important for lymphopoiesis.