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中介激酶抑制进一步激活AML中的超增强剂相关基因

Henry E Pelish¹, Brian B Liau¹, Ioana I Nitulescu¹

¹Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.

|September 30, 2015

概括

在急性髓性白血病 (AML) 中,中介酶CDK8和CDK19抑制超增强剂 (SE) 基因激活. 皮质素A抑制这些激酶,上调SE基因,并在AML细胞中表现出抗白血病作用.

科学领域:

分子生物学
癌症生物学
遗传学

背景情况:

超级增强剂 (SE) 驱动细胞身份和疾病中的关键基因表达.
已知BRD4和CDK7是SE转录的积极调节剂.
与SE相关的基因的负调节因子在很大程度上仍未被描述.

研究的目的:

在急性髓性白血病 (AML) 中识别SE相关基因的负调节者.
研究中介相关激酶CDK8和CDK19在AML中的作用.
评估向这些激酶的治疗潜力.

主要方法:

研究了中介激酶CDK8和CDK19在AML细胞中的功能.
使用皮质素A (CA),是一种自然产品抑制剂的介质激酶.
评估了CA和BRD4抑制剂I-BET151对SE相关基因表达和AML细胞生长的影响.
研究了调节特定转录因子表达的影响.

主要成果:

发现CDK8和CDK19抑制了AML细胞中关键的SE相关基因的激活.
选择性抑制中介激酶,表现出抗白血病活性.
在敏感的AML细胞系中,CA治疗导致了SE相关基因的不成比例上调.
在AML中CA上调瘤抑制和血统控制转录因子 (CEBPA,IRF8,IRF1,ETV6).
抑制BRD4也显示出抗白血病活性,但降低了这些与SE相关的基因.
调节这些转录因子影响了AML细胞生长,表明了剂量敏感性.

结论:

中介酶CDK8和CDK19作为AML中SE相关基因表达的负调节剂.
皮质素A针对这些激酶,为AML提供了潜在的治疗策略.
通过调节SE驱动的基因表达,向介质激酶是AML治疗的新方法.

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