...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Cell Reports >High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML
【24h】

High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML

机译：RNA聚合酶的高分辨率定位确定了t（8; 21）AML中敏感性和对BET抑制剂的抗性机制

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Bromodomain and extra-terminal domain (BET) family inhibitors offer an approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML), as these polymerases are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1,400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8;21) AML. PRO-seq also identified an enhancer 3' to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter, while CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq also identified microRNAs, including MIR29C and MIR29B2, that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was upregulated, and inhibition of BET proteins sensitized t(8:21)-containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET-inhibitor-induced cell death.
机译：溴结构域和末端外结构域（BET）家族抑制剂提供了一种治疗血液系统恶性肿瘤的方法。我们使用精密核运行转录测序（PRO-seq）创建了t（8; 21）急性髓细胞白血病（AML）中整个基因组的活性RNA聚合酶的高分辨率图，因为这些聚合酶对BET抑制剂异常敏感。 PRO-seq识别了1,400个以上的基因，这些基因显示了启动子附近暂停的RNA聚合酶释放受损，包括在t（8; 21）AML中突变的干细胞因子受体酪氨酸激酶KIT。 PRO-seq还鉴定出KIT的增强子3'。染色体构象捕获证实了该增强子与KIT启动子之间的接触，而CRISPRi介导的对该增强子的阻遏损害了细胞的生长。 PRO-seq还鉴定了靶向抗凋亡因子MCL1并被BET抑制剂抑制的microRNA，包括MIR29C和MIR29B2。 MCL1蛋白被上调，并且对BET蛋白的抑制使含t（8:21）的细胞对MCL1的抑制敏感，表明对BET抑制剂诱导的细胞死亡具有抗性的潜在机制。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号