在RNA剪接和表观遗传调节的协调改变驱动白血病发生
Akihide Yoshimi1, Kuan-Ting Lin2, Daniel H Wiseman3,4
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nature
|October 4, 2019
概括
通过改变表观遗传和RNA拼接,IDH2和SRSF2中的突变共同驱动急性髓性白血病. 这项研究提供了第一个功能性证据,表明拼接因子突变引发了骨髓瘤.
科学领域:
- 分子生物学
- 癌症生物学
- 遗传学
背景情况:
- 转录和mRNA前拼接对于基因表达至关重要,在白血病中经常观察到突变.
- 在白血病发生过程中表观遗传调节和拼接之间的相互作用尚不清楚.
- 缺乏功能性证据将RNA剪接因子突变与白血病的发病联系起来.
研究的目的:
- 研究IDH2和SRSF2突变对白血病发生的协调作用.
- 在急性髓性白血病中探索同时发生的表观遗传和拼接变化的功能后果.
- 提供结合因子突变作为骨髓瘤恶性病因的证据.
主要方法:
- 对982名急性髓性白血病患者的转录组分析.
- 使用小鼠模型进行体内研究,以评估骨髓质疏松症和自我更新.
- 对RNA聚合酶II停滞和INTS3基因表达和拼接的分析.
主要成果:
- 在急性髓性白血病中发现的IDH2和SRSF2突变频繁重叠.
- 突变的IDH2和SRSF2的同时表达会导致严重的拼接变化和致命的骨髓.
- 在双变异细胞中观察到INTS3异常拼接,减少INTS3表达和增加RNA聚合酶II停滞.
结论:
- 在白血病的一个子集中,改变的表观遗传状态和拼接之间存在病原性交叉声.
- 结合因子的突变,如SRSF2,可以启动骨髓性恶性瘤的发展.
- 结合体变异调解IDH2突变白血病,突出显示一种新的治疗途径.
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