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在急性髓性白血病中venetoclax耐药性的动态演变,由纵向单细胞RNA-seq揭示

Huan Lu¹, Huafeng Wang², Qiwei Wang¹

¹Department of Hematology of the First Affiliated Hospital, Liangzhu Laboratory, Zhejiang University School of Medicine, Center for Stem Cell and Regenerative Medicine, Hangzhou, 310003, China; Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, 310058, China.

|June 7, 2025

概括

了解急性髓性白血病 (AML) 的耐治疗性是关键. 这项研究揭示了骨髓微环境在venetoclax治疗期间的变化,确定了改善AML患者治疗结果的新策略.

科学领域:

血液学和瘤学研究
单细胞基因组学单细胞基因组学
癌症免疫学癌症免疫学

背景情况:

维内托克拉克斯耐药性是急性髓性白血病 (AML) 治疗的一个主要挑战.
骨髓微环境在治疗耐药性的作用在单细胞分辨率上尚不清楚.
基于Venetoclax的疗法,包括德西他和cytarabine (DAV),用于AML,但耐药性机制需要进一步阐明.

研究的目的:

在AML患者的基于venetoclax的治疗期间,绘制骨髓微环境中的治疗诱导的变化.
确定治疗反应和耐药性的单细胞解决机制.
开发预后特征并确定克服抗性的新疗法策略.

主要方法:

在DAV治疗之前和之后,从AML患者的骨髓样本的配对单细胞RNA测序.
治疗诱导的转录重编程和调节网络变化的系统映射.
在独立患者队列中验证预后签名和治疗目标的功能验证.

主要成果:

具有高HLA类I呈现和增强的CD8+T细胞活性相关的免疫激活与有利的反应.
响应型白血病细胞显示了转移性元素 (TE) 相关的I型干扰素信号的增加.
耐药单细胞AML种群上调糖解和MCL1,绕过BCL2依赖;预后特征确定了对IGF-1R抑制敏感的高风险患者.

结论:

单细胞分析揭示了AML基于venetoclax的治疗期间关键的骨髓微环境动态.
一个新的预后特征预测患者的反应,并确定对IGF-1R抑制的敏感性,以克服耐药性.
通过调节葡萄糖代谢和分化,IGF-1R抑制与DAV疗法协同作用,提供了一个潜在的临床策略.

关键词:

急性骨髓性白血病 (AML) 是一种急性骨髓性白血病.在DAV治疗过程中,使用DAV治疗方法.单细胞RNA测序的一个细胞.治疗耐药性是一种治疗性耐药性.威尼托克拉克斯 (Venetoclax) 是一个属于威尼托克拉克斯的地区.

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