Reducing hyperactivated BAP1 attenuates mutant ASXL1-driven myeloid malignancies in human haematopoietic cells.

Additional sex combs-like 1 (ASXL1) is frequently mutated in a variety of myeloid malignancies, resulting in expression of a C-terminal-truncated ASXL1 protein that confers gain of function on the ASXL1-BAP1 deubiquitinase (DUB) complex. Several studies have reported that hyperactivity of BRCA-1-associated protein 1 (BAP1) in deubiquitinating mono-ubiquitinated histone H2AK119 is one of the critical molecular mechanisms in ASXL1 mutation-driven myeloid malignancies in mice. In this study, we found that human haematopoietic stem and progenitor cells (HSPCs) overexpressing truncated ASXL1 (ASXL1) developed an MDS-like phenotype similar to that induced by overexpression of BAP1. We then used shRNAs targeting BAP1 in ASXL1-overexpressing HSPCs and primary leukaemia cells with ASXL1 mutation, demonstrating that reduced BAP1 expression can partially rescue the pathological consequences. RNA sequencing and chromatin immunoprecipitation coupled with quantitative PCR analyses revealed that reduced BAP1 expression suppressed upregulation of the transcription factors AP-1 and EGR1/2, as well as myeloid dysplasia-associated genes, by retarding H2AK119Ub removal caused by ASXL1 mutation. This study indicates that targeting the hyperactive ASXL1-BAP1 DUB complex can attenuate mutant ASXL1-driven myeloid malignancies in human.