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

Abstract

Additional Sex Combs-Like 1 (<i>ASXL1</i>) is mutated at a high frequency in all forms of myeloid malignancies associated with poor prognosis. We generated a <i>Vav1</i> promoter-driven <i>Flag-Asxl1</i>^<i>Y588X</i> transgenic mouse model, <i>Asxl1</i>^<i>Y588X</i> Tg, to express a truncated FLAG-ASXL1^aa1-587 protein in the hematopoietic system. The <i>Asxl1</i>^<i>Y588X</i> 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 <i>ASXL1</i> 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 <i>Asxl1</i>^<i>Y588X</i> 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 <i>ASXL1</i> truncation mutations in myeloid malignancies.