在BCL2抑制后,CREBBP无活化使B细胞急性淋巴细胞白血病对ferroptotic细胞死亡敏感
Alicia Garcia-Gimenez1,2, Jonathan E Ditcham1,2, Dhoyazan M A Azazi1,2
1Department of Haematology, Cambridge Stem Cell Institute, Cambridge, UK.
Nature communications
|May 20, 2025
概括
针对B细胞急性淋巴细胞白血病 (B-ALL) 的CREBBP突变,使用Venetoclax诱导铁亡. 将BCL2抑制与CREBBP抑制相结合,为高风险B-ALL提供了一个有希望的治疗策略.
科学领域:
- 血液学 血液学 血液学
- 在瘤学瘤学.
- 分子生物学分子生物学
背景情况:
- B细胞急性淋巴细胞白血病 (B-ALL) 在儿科和成人癌症治疗中提出了重大挑战.
- 在CREBBP的突变与高风险的B-ALL和对常规化疗的耐药性有关.
- 对于针对高风险B-ALL病例的新型治疗方法有着至关重要的需求.
研究的目的:
- 为了识别针对CREBBP突变B-ALL.的小分子.
- 研究已识别的药物的作用机制,特别是Venetoclax.
- 探索涉及CREBBP抑制和Venetoclax用于B-ALL治疗的组合疗法.
主要方法:
- 使用具有或没有CREBBP突变的同源人类B-ALL细胞系进行了向药物选.
- 利用了BCL2抑制剂Venetoclax,并评估了它对细胞死亡途径 (细胞亡与铁亡) 的影响.
- 研究CREBBP突变细胞和抵抗机制的细胞特征 (细胞循环,新陈代谢,脂质组成,氧化应激反应).
- 在体外和体内评估了结合CREBBP抑制与Venetoclax的疗效.
主要成果:
- 鉴定出Venetoclax是CREBBP突变B-ALL的强有力的抑制剂,通过非正规机制诱导铁亡.
- 在CREBBP突变细胞中表现出明显的细胞脆弱性,包括改变的新陈代谢和氧化应激反应,这使它们易受铁亡.
- 证明了小分子抑制CREBBP使B-ALL细胞对Venetoclax诱导的铁亡敏感,无论它们的突变状态如何.
- 在体外和体外模型中显示了组合疗法的有效性.
结论:
- 维内托克拉克斯代表了对CREBBP突变B-ALL的有前途的治疗剂,通过铁灭作用.
- 通过抑制CREBBP,可以克服Venetoclax的耐药性,并通过诱导铁亡来增强其疗效.
- 抑制CREBBP和Venetoclax的组合为B-ALL提供了一种新且可能广泛适用的治疗策略.
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