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在急性髓性白血病中,m6a和NuRD复合体调节单细胞分化和对BCL2/BCL2L1抑制剂的抗性

Jackson Brim-Edwards¹, Karen Morris¹, Quinlan Morrow¹

¹Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health and Science University, Portland, OR.

|October 16, 2025

概括

在急性髓性白血病 (AML) 中对venetoclax的耐药性可以通过向RBM15和ZMYND8.8来克服. 这些因素通过改变BCL2家族表达和促进细胞分化来调解耐药性.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
遗传学是一个遗传学.

背景情况:

前线venetoclax治疗改善了急性髓性白血病 (AML) 的结果.
威尼托克拉克斯耐药性是一个重大的临床挑战,通常是由抗亡BCL2家族蛋白质的改变表达所驱动的.
出现了替代的生存途径,减少了对BCL2的依赖,并赋予了抵抗力.

研究的目的:

研究介导抗BCL2抑制剂的遗传因素,如venetoclax和双重BCL2/BCL2L1抑制剂.
确定急性髓性白血病中抗性的新机制.
探索RNA修饰和染色质重塑在耐药性中的作用.

主要方法:

基于CRISPR的全基因组扰动屏幕被用来识别遗传依赖.
研究了基因干扰对细胞对venetoclax和AZD4320的反应的影响.
在AML患者样本中分析了基因表达和分化标志物.

主要成果:

N6-甲基氨酸 (m6A) 编写器RBM15和NuRD复杂交互器ZMYND8被确定为抗性的新媒体.
RBM15或ZMYND8的丢失使得它们对venetoclax和AZD4320都产生了耐药性.
减少RBM15或ZMYND8的表达,与单细胞分化和AML患者体外抗药性相关.

结论:

在AML中,RBM15和ZMYND8在调解对BCL2家族抑制剂的耐药性方面发挥着关键作用.
针对这些因素可能是克服药物耐药性的治疗策略.
这些发现揭示了AML中以前未被描述的抗药性机制.

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