TP63融合驱动多复杂增强剂重新连接,淋巴发育和EZH2依赖
Gongwei Wu1,2, Noriaki Yoshida1, Jihe Liu3
1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Science translational medicine
|September 20, 2023
概括
涉及瘤蛋白p63基因 (TP63) 的基因融合驱动淋巴瘤的发展. 这些TP63融合招募了表观遗传修饰剂,从而对EZH2抑制产生了脆弱性,这是淋巴瘤患者有前途的治疗策略.
科学领域:
- 血液学 血液学 血液学
- 在瘤学瘤学.
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 在各种淋巴瘤中观察到涉及瘤蛋白p63基因 (TP63) 的基因融合.
- 这些TP63融合与患者的预后不佳有关,缺乏向治疗.
- TP63融合的精确功能和瘤机制在很大程度上是未知的.
研究的目的:
- 阐明TP63融合在淋巴瘤中的致癌作用和分子机制.
- 为了确定 TP63 融合的淋巴瘤的潜在治疗点.
主要方法:
- 开发表达共同的TBL1XR1::TP63融合的转基因小鼠模型.
- 对表观遗传修饰剂招募和下游基因表达的分析.
- 在临床前模型和患者中使用治疗剂valemetostat对EZH2抑制的评估.
主要成果:
- 表达TBL1XR1::TP63的转基因小鼠产生了与人类T细胞和B细胞淋巴瘤相似的多种淋巴瘤.
- 发现TP63的融合可以招募NCoR-HDAC3和KMT2D表观遗传综合体,这对淋巴瘤细胞存活至关重要.
- TBL1XR1::TP63局部化到增强剂,对MYC和PRC2组件进行上调 (EED,EZH2).
- 瓦莱梅托斯塔特治疗有效地抑制了小鼠模型中的淋巴瘤,异种移植和患者衍生的异种移植.
- 一名患有TP63重组淋巴瘤的患者对瓦莱梅托斯塔特表现出快速的积极反应.
结论:
- TP63融合作为瘤基因,对淋巴瘤的发病过程至关重要.
- TP63融合协调表观遗传修饰,导致对EZH2.2的依赖.
- 抑制EZH2代表了TP63融合驱动淋巴瘤患者的可行治疗策略.
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