HDAC3-YY1-RAB5A轴通过调节骨髓 stromal 细胞中的线粒体平衡来重塑AML支持的利基
Chao He1,2, Yue Xiong1,3, Yuqing Zeng1
1School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, China.
Cell death & disease
|July 7, 2025
概括
在骨髓 stromal 细胞 (BMSCs) 中准基因组脱乙酶3 (HDAC3) 减少白血病支持炎症,并增强急性髓性白血病 (AML) 治疗中的耐药性.
科学领域:
- 血液学 血液学 血液学
- 细胞生物学 细胞生物学
- 癌症生物学 癌症生物学
背景情况:
- 急性髓性白血病 (AML) 和骨髓 stromal 细胞 (BMSCs) 之间的相互作用对于白血病的进展和耐药性至关重要.
- 这种相互作用背后的机制及其在创造亲白血病利基中的作用尚未完全理解.
研究的目的:
- 阐明基因组脱乙酶3 (HDAC3) 在BMSCs中调节骨髓微环境并影响AML进展的作用.
- 调查针对BMSC中的HDAC3作为AML治疗策略的潜力.
主要方法:
- 针对炎症表型的AML患者衍生的BMSCs的表征.
- 通过RAB5A.A.对HDAC3在调节线粒体反应性氧物种 (ROS) 生产和线粒体衰变中的作用进行研究.
- 通过转录因子YY1.1.对HDAC3通过转录因子YY1.1.对RAB5A表达的调节进行分析.
- 评估HDAC3抑制对BMSC衰老,ROS产生,AML细胞存活率和耐药性的影响,包括与venetoclax的协同作用.
主要成果:
- 来自AML患者的BMSCs显示了一个超炎症的表型.
- 在BMSC中,HDAC3通过通过RAB5A抑制线粒体细胞的产生,从而促进线粒体ROS的产生,而RAB5A通过YY1.1进行调节.
- 过度的ROS加速了BMSC衰老,并促进了与衰老相关的分泌表型,创造了一个高炎症的利基,激活AML细胞中的NF-κB,增强生存和耐药性.
- 在BMSC中抑制HDAC3可降低ROS,延缓衰老,降低AML的扩散,并与venetoclax协同作用.
结论:
- 在BMSC中的HDAC3通过ROS生产和BMSC衰老驱动了一种亲白血病骨髓利基.
- 针对BMSC中的HDAC3提供了一种新的治疗方法,以重塑AML微环境并克服耐药性.
- 在BMSC中抑制HDAC3显示出对AML的组合治疗的潜力,提高了像venetoclax这样的药物的疗效.
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