[Molecular mechanisms by which the mutant ASXL1/BAP1 complex aggravates myeloid leukemia].

Mutations in ASXL1, which occur frequently in myeloid neoplasms, often confer poor prognosis. Despite their clinical importance, the precise molecular mechanisms underlying the contribution of mutant ASXL1 to cancer pathogenesis remain to be elucidated. Thus, we analyzed the roles of the hyperactive complex formed by mutant ASXL1 and the deubiquitinase BAP1 in promoting myeloid leukemogenesis. BAP1 expression resulted in the stabilization and increased monoubiquitination of mutant but not wildtype ASXL1. Monoubiquitination of mutant ASXL1 enhanced the catalytic function of BAP1, resulting in a profound reduction in H2AK119ub by counteracting the PRC1 complex. The mutant ASXL1-BAP1 hyperactive complex impaired the multi-lineage differentiation of hematopoietic progenitor cells and accelerated myeloid leukemogenesis. Mechanistically, the mutant ASXL1/BAP1 complex induced the upregulation of HOXA5, HOXA7, HOXA9, and IRF8 via a reduction in H2AK119ub. Importantly, BAP1 depletion inhibited the leukemogenicity of mutant ASXL1-expressing myeloid leukemia cells and MLL-rearranged leukemia cells by reducing the expression levels of HOXA5, HOXA7, and HOXA9. Our findings highlight the potential of BAP1 as a therapeutic target in a broad range of myeloid neoplasms.