在急性白血病中通过ENL YEATS域进行转录控制
Michael A Erb1, Thomas G Scott1, Bin E Li2,3,4
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Nature
|February 28, 2017
概括
研究人员发现ENL对于急性白血病的扩散至关重要. 针对其YEATS领域提供了对这种具有挑战性的癌症的潜在新疗法.
科学领域:
- 癌症学
- 分子生物学
- 遗传学
背景情况:
- 涉及MLL基因的重复染色体转移会产生融合瘤基因,导致具有不良预后的侵袭性急性白血病.
- 目前针对MLL驱动的白血病的治疗方法不足,强调需要新的治疗点.
- 染色体调节剂与MLL驱动的白血病有关,这表明对转录控制的依赖.
研究的目的:
- 通过全基因组查,识别用于MLL-AF4阳性急性白血病的新基因.
- 阐明已识别的ENL基因在白血病发生和转录调节中的机制性作用.
- 探索针对ENL的治疗潜力.
主要方法:
- 在MLL-AF4阳性急性白血病细胞系中进行基因尺度CRISPR-Cas9功能丧失查.
- 针对ENL蛋白质降解的化学遗传策略.
- 全基因组RNA聚合酶II启动和延长的分析.
- 对YEATS染色体读取器域在白血病生长中的作用的评估.
主要成果:
- 在实验室和体内确定ENL是MLL- AF4阳性的急性白血病细胞增殖所需的基因.
- 在活性基因中,急性ENL消耗显著抑制了RNA聚合酶II的启动和延伸.
- 发现ENL的YEATS染色体读取域对白血病细胞生长至关重要.
- 在特定的基因中,ENL表现出不成比例的负载,影响转录动态.
结论:
- 在MLL引起的急性白血病中,ENL是关键的依赖因素.
- 对这种侵袭性白血病来说,破坏ENL功能,特别是 YEATS领域,是一个有前途的治疗策略.
- 这些发现为针对白血病发生的ENL提供了机制性的理由.
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