通过PRMT1介导的代谢重编程促进了白血病发生
Hairui Su1, Yong Sun2,3, Han Guo4
1Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, School of Medicine, Birmingham, United States.
eLife
|August 13, 2025
概括
蛋白质氨酸甲基转移酶1 (PRMT1) 驱动急性巨核细胞白血病 (AMKL) 通过促进糖解和阻碍脂肪酸氧化. 抑制PRMT1或准葡萄糖代谢为这种癌症提供了治疗策略.
科学领域:
- 在瘤学瘤学.
- 癌症新陈代谢 癌症新陈代谢
- 分子生物学分子生物学
背景情况:
- 蛋白质氨酸甲基转移酶1 (PRMT1) 在癌症中经常过度表达,与患者生存率差相关.
- 急性巨核细胞白血病 (AMKL) 是急性髓性白血病的一个亚型,具有特定的分子驱动因素.
- 白血病细胞系内PRMT1表达的异质性表明,不同的亚种群可能会推动疾病的进展.
研究的目的:
- 研究PRMT1在AMKL病变发生中的作用及其对细胞代谢的影响.
- 在临床前AMKL模型中评估PRMT1抑制的治疗潜力.
- 阐明PRMT1在白血病细胞中调节的代谢途径.
主要方法:
- 使用了一种具有异质Prmt1表达的小鼠AMKL细胞系 (6133).
- 使用PRMT1抑制剂 (MS023) 进行治疗干预.
- 进行海马分析以评估细胞呼吸和糖解.
- 进行了代谢和流动细胞计分析,以评估脂质代谢.
- 给了2-deoxy-D-glucose并进行了基因救援实验.
主要成果:
- 在AMKL细胞亚群中高PRMT1表达对于体内白血病的发展至关重要.
- 通过MS023有效治疗PRMT1驱动的AMKL来抑制PRMT1.
- PRMT1上调糖解 (增加细胞外酸化率,葡萄糖消耗,乳酸生产) 和下调脂肪酸氧化 (减少氧气消耗率,减少CPT1A表达).
- PRMT1促进了细胞内脂质的积累.
- 葡萄糖模拟治疗延迟了AMKL的进展并诱导了分化;Cpt1a再表达挽救了扩散.
结论:
- 通过增强糖解和抑制脂肪酸氧化,PRMT1促进AMKL的扩散.
- 向PRMT1或葡萄糖代谢是AMKL的一个有前途的治疗策略.
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