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该ESCRT蛋白CHMP5通过控制BRD4-p300-依赖转录促进T细胞白血病

Katharine Umphred-Wilson^1,2, Shashikala Ratnayake^3,4, Qianzi Tang^5,4

¹Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

bioRxiv : the preprint server for biology

|February 14, 2024

概括

运输所需的内体组分复合体 (ESCRT) 蛋白CHMP5在T细胞急性淋巴细胞白血病 (T-ALL) 中发挥着至关重要的核心作用. 失去CHMP5会损害T-ALL转录程序,减少化学抵抗和疾病诱导.

科学领域:

分子生物学分子生物学
癌症生物学癌症生物学
细胞生物学细胞生物学

背景情况:

瘤基因活动改变细胞转录,通过不太了解的机制在癌细胞中产生依赖性.
由于T细胞急性淋巴细胞白血病 (T-ALL) 的进展依赖于特定的转录网络.

研究的目的:

为了研究CHMP5的作用,一种需要运输 (ESCRT) 蛋白的内体组分复合体,在T-ALL的转录调节中发挥作用.
阐明CHMP5影响T-ALL转录程序的机制及其对疾病发病的影响.

主要方法:

使用了T-ALL.的人类和小鼠模型.
研究了CHMP5.5的核功能.
在增强剂和超增强剂中评估了p300对BRD4的招募.
测量了H3K27的乙化水平.
分析的RNA聚合酶II暂停释放.
评估了CHMP5缺乏对抗化学性和瘤性NOTCH1诱导的T-ALL的影响.

主要成果:

确定了CHMP5在建立和维护T-ALL转录程序中的重要核心作用.
证明核CHMP5在增强剂/超增强剂中增加p300的BRD4招募,从而增强H3K27乙化.
表明CHMP5的损失降低了BRD4占用率,损害了RNA聚合酶II暂停释放,并降低了MYC.等关键T-ALL基因的调节.
在人体T-ALL细胞中,CHMP5缺乏减轻了化学抵抗,并且在体内通过瘤性NOTCH1取消了T-ALL诱导.

结论:

该ESCRT蛋白CHMP5是驱动T-ALL的转录机械的关键核调节器.
通过调节增强剂活性和基因转录,CHMP5促进T-ALL基因程序.
向CHMP5代表了T-ALL.的潜在治疗策略.

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