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稳定BAP1在ASXL1功能获得突变白血病中的表观遗传靶向治疗

原文发布日期：2021-05-25

英文摘要：

摘要翻译：

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文章：

稳定BAP1在ASXL1功能获得突变白血病中的表观遗传靶向治疗

Epigenetic targeted therapy of stabilized BAP1 in ASXL1 gain-of-function mutated leukemia

原文发布日期：2021-05-25

英文摘要：

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.

摘要翻译：

ASXL1突变体编码BAP1历史H2A去乙酰化酶复合体中的一部分，在人类髓系白血病中有发生，并与不良预后一致。然而，尚不清楚这些突变如何通过影响BAP1活性进而驱动白血病的发生机制。我们在此证明，原本被提以为是去功能化的稳定化突变，ASXL1的癌症相关 frameshift 突变体实际上编码稳定的截短增强功能蛋白。截断型ASXL1增加了BAP1蛋白的稳定性，并增强了BAP1在染色体上附着的能力，从而促进促白细胞转录标志物的表达。通过生化筛选实验，我们发现抑制BAP1催化活性的抑制剂，这些抑制剂能够抑制截断-ASXL1引起的促白细胞基因表达，在体内抑制肿瘤进展。这项研究为我们阐明了白血病发生机制中ASXL1突变体分子机制 represents a breakthrough and identified small-molecular catalytic inhibitors of BAP1作为潜在针对白血病的靶向治疗。