SETBP1 mutations drive leukemic transformation of ASXL1-mutated MDS

Abstract

Recently, mutations of additional sex comb-like 1 (ASXL1) have been identified as an independent poor prognostic factor in MDS patients. We previously demonstrated that C-terminal–truncating ASXL1 mutations (ASXL1-MT) inhibited myeloid differentiation and induced MDS-like disease in mice by inhibiting polycomb repressive complex 2–mediated methylation of histone H3K27. Intriguingly, the patients with ASXL1 mutation have significantly higher incidences of concurrent SET binding protein 1 (SETBP1) mutation than those with wild-type ASXL1, which prompted us to investigate whether SETBP1 mutation plays a critical role in leukemic transformation of MDS.