恢复TET2功能 阻断异常自我更新和白血病进展
Luisa Cimmino1, Igor Dolgalev2, Yubao Wang3
1Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA.
Cell
|August 22, 2017
概括
恢复TET2功能可以逆转白血病干细胞的生长. 维生素C模仿这种作用,通过增强对PARP抑制剂的敏感性,为TET2缺乏的癌症提供潜在的治疗方法.
科学领域:
- 血液学
- 癌症生物学
- 表观遗传学
背景情况:
- 在克隆造血,骨髓位综合征 (MDS) 和急性骨髓性白血病 (AML) 中,TET2功能丧失突变很常见.
- TET2 缺乏与DNA高甲基化表型有关,影响了造血干细胞和原始细胞 (HSPC) 的功能.
研究的目的:
- 研究TET2缺乏在维持白血病干细胞中的作用.
- 探索TET2缺乏性白血病的治疗策略.
主要方法:
- 创建了一个可逆转基因RNAi小鼠模型来研究Tet2恢复.
- 使用维生素C补充剂在体外和体内模拟TET2功能.
- 对HSPC自我更新,白血病殖民地形成和患者衍生异种移植 (PDX) 的评估影响.
- 分析了DNA甲基化模式和基因表达特征.
主要成果:
- 在缺少Tet2的模型中逆转异常的HSPC自我更新.
- 维生素C增强了5- 甲基细胞因子的形成,抑制了人体细胞和PDX的白血病生长.
- 维生素C诱导DNA低甲基化和调节TET2依赖基因表达.
- 维生素C治疗使白血病细胞对PARP抑制产生敏感性.
结论:
- TET2 缺陷有助于白血病干细胞的维持.
- 维生素C可以替代TET2,为TET2缺乏性白血病提供一种潜在的治疗方法.
- 与维生素C和PARP抑制剂的联合治疗对向TET缺乏症的癌症具有前景.
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