Srsf2P95H/+ mutation exacerbates Asxl1Y588XTg-induced leukemogenesis

Additional sex comb-like 1 (ASXL1) is frequently mutated in a spectrum of myeloid malignancies and is associated with poor prognosis. Cancer genome sequencing found that AXL1 mutations frequently co-occur with splicing factors’ mutations (SRSF2, U2AF1, ZRZR2 and SF3B1) in myeloid malignancies. Several studies have reported that Patients with both ASXL1 and splicing mutations have a significantly worse prognosis than those with a single type of mutation, but the mechanisms largely remain to be elucidated. Here we constructed an ASXL1 and SRSF2 co-mutated mouse model and found that Srsf2P95H/+ mutation exacerbated Asxl1Y588XTg-induced leukemogenesis. Mechanistically, the co-existence of ASXL1 mutation and SRSF2 mutation altered the function of hematopoietic stem and progenitor cells and resulted in skewed myeloid differentiation. RNA-seq for bone marrow Lin-cKit+Sca-1+ cells from WT (n=4), Asxl1Y588XTg (n=4), Srsf2P95H/+ (n=4) and Asxl1Y588XTg;SRSF2P95H/+ (n=3) mice.