替代转录启动导致癌症中新型ALK异型的表达
Thomas Wiesner1,2, William Lee3,4, Anna C Obenauf5
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
Nature
|October 8, 2015
概括
在11%的黑色素瘤中,一种新型的形淋巴瘤激酶 (ALK) 异型 (ALK(ATI) 是通过替代转录启动而非基因变化而被激活的. 这一发现为癌症治疗提供了新的治疗点.
科学领域:
- 癌症学
- 分子生物学
- 遗传学
背景情况:
- 除了遗传异常之外,瘤基因激活的机制尚不清楚.
- 形淋巴瘤激酶 (ALK) 是已知的瘤基因,但其激活途径尚未完全阐明.
研究的目的:
- 确定和描述癌症中的新型癌基因激活机制.
- 研究新发现的ALK异型在黑色素瘤和其他癌症中的作用.
主要方法:
- 转录组分析以识别新型ALK异型.
- 染色体免疫沉以评估活性转录标记 (H3K4me3,RNA聚合酶II).
- 在小鼠体内细胞增殖试验和体内瘤生成模型.
主要成果:
- 鉴定出一种新型的ALK异型,ALK(ATI),其发源于19号内核中的新型替代转录发源点.
- 在大约11%的黑色素瘤中和偶尔在其他癌症中发现了ALK ((ATI),但在正常组织中没有发现.
- 在ALK位点的基因异常独立,促进了瘤信号传递,细胞增殖和瘤发生.
结论:
- 新的替代转录启动代表了癌症瘤基因激活的新机制.
- 它的活性可以被ALK抑制剂抑制.
- 向ALK ((ATI)) 可能有利于患有ALK ((ATI)) 表达瘤的患者.
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