抑制PSTK激活cGAS-STING,从而导致白血病干细胞中的铁细胞死亡
Lingli He1,2,3, Ting Zhao1,2,3, Wei Zhong Leong1,2,3
1Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA.
Blood
|February 6, 2025
概括
在急性髓性白血病 (AML) 中向索转移RNA激酶 (PSTK) 损害了癌细胞的生长和自我更新. 这种方法有望克服化疗耐药性,并通过诱导铁亡来预防复发.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 急性髓性白血病 (AML) 呈现分化停止,并依赖于氧化代谢.
- 在AML中的遗传多样性具有共同特征.
- 白血病干细胞对于AML的持续性和复发至关重要.
研究的目的:
- 在AML中确定新的治疗点.
- 研究素转移RNA激酶 (PSTK) 在AML中的作用.
- 制定策略来克服AML中的化疗耐药性.
主要方法:
- 在AML细胞中进行表型CRISPR-CRISPR相关蛋白9 (CRISPR-Cas9) 查.
- 药理上抑制PSTK (PSTKi) 在体外和体内.
- 大鼠和患者衍生异种移植模型的AML.
- 对活性氧物种 (ROS),线粒体DNA释放和cGAS-STING通路激活的分析.
- 评估铁代谢和铁灭诱导.
主要成果:
- 在CRISPR-Cas9查中,PSTK被确定为AML的关键.
- 抑制PSTK会影响AML细胞生长和白血病干细胞自我更新.
- 定时PSTKi在体内有效向耐化疗AML,对恶性细胞具有选择性.
- PSTKi诱导了ROS,线粒体DNA释放和cGAS-STING激活,破坏了铁代谢并增加了铁亡.
- 确定了一个自我强化的PSTK-cGAS-STING-ROS循环,导致白血病干细胞的氧化危机和ferroptotic死亡.
结论:
- 在AML中,PSTK是关键的标,对蛋白生物合成至关重要.
- 向PSTK诱导AML干细胞中的致命氧化危机和铁亡.
- 定时PSTKi提供了一种潜在的策略,通过消除残留疾病和预防复发来增强化疗.
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