文章：

ASXL1突变与特定的表观基因组改变相关，这些改变导致对维奈托克和阿扎胞苷的敏感性

ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine

原文发布日期：2021-09-21

DOI: 10.1038/s41408-021-00541-0

类型: Article

开放获取: 是

英文摘要：

The BCL2-inhibitor, Venetoclax (VEN), has shown significant anti-leukemic efficacy in combination with the DNMT-inhibitor, Azacytidine (AZA). To explore the mechanisms underlying the selective sensitivity of mutant leukemia cells to VEN and AZA, we used cell-based isogenic models containing a common leukemia-associated mutation in the epigenetic regulator ASXL1. KBM5 cells with CRISPR/Cas9-mediated correction of the ASXL1G710X mutation showed reduced leukemic growth, increased myeloid differentiation, and decreased HOXA and BCL2 gene expression in vitro compared to uncorrected KBM5 cells. Increased expression of the anti-apoptotic gene, BCL2, was also observed in bone marrow CD34+ cells from ASXL1 mutant MDS patients compared to CD34+ cells from wild-type MDS cases. ATAC-sequencing demonstrated open chromatin at the BCL2 promoter in the ASXL1 mutant KBM5 cells. BH3 profiling demonstrated increased dependence of mutant cells on BCL2. Upon treatment with VEN, mutant cells demonstrated increased growth inhibition. In addition, genome-wide methylome analysis of primary MDS samples and isogenic cell lines demonstrated increased gene-body methylation in ASXL1 mutant cells, with consequently increased sensitivity to AZA. These data mechanistically link the common leukemia-associated mutation ASXL1 to enhanced sensitivity to VEN and AZA via epigenetic upregulation of BCL2 expression and widespread alterations in DNA methylation.
 

摘要翻译： 

BCL2抑制剂Venetoclax（VEN）与DNMT抑制剂阿扎胞苷（AZA）联用显示出显著抗白血病疗效。为探究突变白血病细胞对VEN和AZA选择性敏感的机制，我们利用表观遗传调控因子ASXL1携带常见白血病相关突变的同基因细胞模型进行研究。与未校正的KBM5细胞相比，通过CRISPR/Cas9技术校正ASXL1G710X突变的KBM5细胞在体外表现出白血病生长减弱、髓系分化增强及HOXA与BCL2基因表达下调。在ASXL1突变型骨髓增生异常综合征（MDS）患者的骨髓CD34+细胞中，同样观察到抗凋亡基因BCL2的表达水平高于野生型MDS患者的CD34+细胞。ATAC测序显示ASXL1突变型KBM5细胞的BCL2启动子区域染色质开放程度增加。BH3分析表明突变细胞对BCL2的依赖性增强，VEN处理后突变细胞生长抑制更为明显。此外，对原代MDS样本及同基因细胞系的全基因组甲基化分析显示，ASXL1突变细胞中基因体甲基化水平升高，进而导致对AZA的敏感性增强。这些数据从机制上阐明了ASXL1这一常见白血病相关突变通过表观遗传上调BCL2表达及广泛改变DNA甲基化，从而增强对VEN与AZA敏感性的生物学通路。

原文链接：

ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine