Additional Sex Combs-Like 1 ( ASXL1 ) is mutated at a high frequency in all forms of myeloid malignancies associated with poor prognosis. We generated a Vav1 promoter-driven Flag-Asxl1 Y588X transgenic mouse model, Asxl1 Y588X Tg, to express a truncated FLAG-ASXL1 aa1-587 protein in the hematopoietic system. The Asxl1 Y588X 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 ASXL1 mutations. ATAC- and RNA-sequencing analyses revealed that the ASXL1 aa1-587 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 aa1-587 acquired an interaction with BRD4. An epigenetic drug screening demonstrated a hypersensitivity of Asxl1 Y588X Tg bone marrow cells to BET bromodomain inhibitors. This study demonstrates that ASXL1 aa1-587 plays a gain-of-function role in promoting myeloid malignancies. Our model provides a powerful platform to test therapeutic approaches of targeting the ASXL1 truncation mutations in myeloid malignancies.