Loss-of-function Additional sex combs like 1mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia

The Additional sex combs like 1 (Asxl1)gene is 1 of 3 mammalian homologs of the Additional sex combs (Asx)gene of Drosophila. Asxis unusual because it is required to maintain both activation and silencing of Hoxgenes in flies and mice. Asxl proteins are characterized by an amino terminal homology domain, by interaction domains for nuclear receptors, and by a C-terminal plant homeodomain protein-protein interaction domain. A recent study of patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) revealed a high incidence of truncation mutations that would delete the PHD domain of ASXL1. Here, we show that Asxl1is expressed in all hematopoietic cell fractions analyzed. Asxl1knockout mice exhibit defects in frequency of differentiation of lymphoid and myeloid progenitors, but not in multipotent progenitors. We do not detect effects on hematopoietic stem cells, or in peripheral blood. Notably, we do not detect severe myelodysplastic phenotypes or leukemia in this loss-of-function model. We conclude that Asxl1 is needed for normal hematopoiesis. The mild phenotypes observed may be because other Asxlgenes have redundant function with Asxl1, or alternatively, MDS or oncogenic phenotypes may result from gain-of-function Asxlmutations caused by genomic amplification, gene fusion, or truncation of Asxl1.