Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies.

Additional Sex Combs-Like 1 () is mutated at a high frequency in all forms of myeloid malignancies associated with poor prognosis. We generated a promoter-driven transgenic mouse model, Tg, to express a truncated FLAG-ASXL1 protein in the hematopoietic system. The Tg mice had an enlarged hematopoietic stem cell (HSC) pool, shortened survival, and predisposition to a spectrum of myeloid malignancies, thereby recapitulating the characteristics of myeloid malignancy patients with mutations. ATAC- and RNA-sequencing analyses revealed that the ASXL1 truncating protein expression results in more open chromatin in cKit cells compared with wild-type cells, accompanied by dysregulated expression of genes critical for HSC self-renewal and differentiation. Liquid chromatography-tandem mass spectrometry and coimmunoprecipitation experiments showed that ASXL1 acquired an interaction with BRD4. An epigenetic drug screening demonstrated a hypersensitivity of Tg bone marrow cells to BET bromodomain inhibitors. This study demonstrates that ASXL1 plays a gain-of-function role in promoting myeloid malignancies. Our model provides a powerful platform to test therapeutic approaches of targeting the truncation mutations in myeloid malignancies.