一个单一的瘤增强剂重组导致白血病的同时发生的EVI1和GATA2放松调节
Stefan Gröschel1, Mathijs A Sanders2, Remco Hoogenboezem2
1Department of Hematology, Erasmus University Medical Center, Rotterdam, 3015 GE, the Netherlands; Department of Internal Medicine III, Ulm University Hospital, 89081 Ulm, Germany.
Cell
|April 8, 2014
概括
在AML中的染色体重排可以通过重新定位一个调节元件来激活EVI1基因,从而导致癌症. 切除这种增强剂阻止了癌细胞的生长,提供了一个潜在的治疗点.
科学领域:
- 遗传学 遗传学 是一个
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 染色体重组,特别是那些没有基因融合的染色体,都与白血病发生有关.
- 干细胞调节器EVI1的异常表达是急性髓性白血病 (AML) 的标志,其中inv3 / t3 / t3 / 3).
研究的目的:
- 研究3q重组导致AML异常EVI1表达的机制.
- 探索增强剂重新定位在基因放松调节和白血病发生中的作用.
主要方法:
- 使用了功能性基因组学和基因组工程技术.
- 在AML细胞中进行了宫外增强体的基因组切除.
- 用药理学BET抑制来复制增强剂切除的效果.
主要成果:
- 无论是inv(3) 和t(3;3) 的重排,都被证明可以重新定位一个远端GATA2增强剂,异位激活EVI1.1.
- 这些重新排列也导致GATA2功能哈普洛缺陷.
- 宫外增强体的基因组切除导致EVI1沉默,AML细胞生长抑制和分化.
- 药理学BET抑制模仿了增强器切除的效果.
结论:
- 单个增强剂的染色体重新定位可以放松两个远端基因EVI1和GATA2的调节,从而推动白血病发生.
- 针对子宫外增强剂或相关途径 (例如,BET抑制) 显示了3q重组的AML的治疗潜力.
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