用EZH2激活突变的淋巴瘤治疗策略之一是EZH2抑制
Michael T McCabe1, Heidi M Ott, Gopinath Ganji
1Cancer Epigenetics Discovery Performance Unit, Cancer Research, Oncology R&D, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, USA.
Nature
|October 12, 2012
概括
该研究表明,用GSK126抑制EZH2甲基转移酶活性有效治疗EZH2突变淋巴瘤. 这种有针对性的方法减少了细胞系和小鼠模型中的瘤生长,提供了一个有前途的新疗法.
科学领域:
- 表观遗传学和基因调控
- 癌症生物学 癌症生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 基因组体的翻译后修改调节了染色质结构和基因表达.
- EZH2是PRC2的关键成分,甲基化H3K27以抑制基因;其过度表达与癌症有关.
- 在淋巴瘤中发现了特定的EZH2突变 (Y641,A677),导致H3K27me3.3.增加.
研究的目的:
- 在EZH2突变淋巴瘤中研究直接EZH2甲基转移酶抑制的疗效.
- 在EZH2突变淋巴瘤的临床前模型中评估选择性EZH2抑制剂GSK126.
主要方法:
- 利用了GSK126,一种针对EZH2甲基转移酶活性的小分子抑制剂.
- 评估了GSK126对全球H3K27me3水平和细胞系基因表达的影响.
- 在小鼠中评估了GSK126在抑制EZH2突变DLBCL细胞系和异种移植的增殖方面的疗效.
主要成果:
- 治疗GSK126降低了全球H3K27me3水平,并重新激活了被静止的PRC2目标基因.
- GSK126在EZH2突变DLBCL细胞系中显著抑制了增殖.
- 在体内,GSK126显著抑制了EZH2突变DLBCL异种移植的生长.
结论:
- 药理上抑制EZH2甲基转移酶活性对EZH2突变淋巴瘤有效.
- GSK126代表了治疗EZH2突变B细胞淋巴瘤的潜在治疗策略.
- 准EZH2为新型淋巴瘤治疗提供了一个有希望的途径.
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