Mutations of ASXL1, encoding a component of the BAP1 histone H2A deubiquitinase complex, occur in human myeloid neoplasms and are uniformly associated with poor prognosis. However, the precise molecular mechanisms through which ASXL1 mutations alter BAP1 activity and drive leukemogenesis remain unclear. Here we demonstrate that cancer-associated frameshift mutations in ASXL1, which were originally proposed to act as destabilizing loss-of-function mutations, in fact encode stable truncated gain-of-function proteins. Truncated ASXL1 increases BAP1 protein stability, enhances BAP1 recruitment to chromatin and promotes the expression of a pro-leukemic transcriptional signature. Through a biochemical screen, we identified BAP1 catalytic inhibitors that inhibit truncated-ASXL1-driven leukemic gene expression and impair tumor progression in vivo. This study represents a breakthrough in our understanding of the molecular mechanisms of ASXL1 mutations in leukemia pathogenesis and identifies small-molecular catalytic inhibitors of BAP1 as a potential targeted therapy for leukemia.

编码 BAP1 组蛋白 H2A 去泛素化酶复合体成分的ASXL1突变发生在人类骨髓肿瘤中，并且与预后不良相关。然而，ASXL1突变改变 BAP1 活性并驱动白血病发生的确切分子机制仍不清楚。在这里，我们证明了ASXL1中与癌症相关的移码突变，最初被提议作为不稳定的功能丧失突变，实际上编码稳定的截短的功能获得蛋白。截短的 ASXL1 增加了 BAP1 蛋白的稳定性，增强了 BAP1 向染色质的募集，并促进了促白血病转录特征的表达。通过生化筛选，我们确定了 BAP1 催化抑制剂可抑制截短的 ASXL1 驱动的白血病基因表达并在体内损害肿瘤进展。这项研究代表了我们对ASXL1突变在白血病发病机制中的分子机制的理解的突破，并将 BAP1 的小分子催化抑制剂确定为白血病的潜在靶向治疗。