发生RAS突变的白血病干细胞导致对venetoclax的临床耐药性
Junya Sango1,2,3,4,5, Saul Carcamo1,2,3,4,5,6, Maria Sirenko7,8
1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nature
|October 31, 2024
概括
RAS突变是急性髓性白血病 (AML) 的晚期事件,需要先前的突变. 突变的RAS转化了特定的骨髓原生细胞,影响了白血病干细胞 (LSC) 层次和静脉抗性.
科学领域:
- 血液学
- 癌症生物学
- 分子瘤学
背景情况:
- 在急性髓性白血病 (AML) 的进展或复发中,经常会发现RAS突变.
- 在AML中获得RAS突变的生物学原因尚不清楚.
研究的目的:
- 调查AML中RAS突变的强制性晚期获取的机制基础.
- 阐明RAS突变如何影响白血病干细胞 (LSC) 层次和治疗反应.
主要方法:
- 利用人类白血病发生模型研究突变获得的时间顺序.
- 在特定的造血细胞中分析了突变RAS的转化潜力.
- 在RAS突变型与RAS野生型LSC中检查了BCL2家族基因表达和venetoclax敏感性.
主要成果:
- 在AML中,RAS突变是强制性的晚期事件,依赖于合作突变.
- 突变的RAS特异性地转化了具有先前驱动的颗粒细胞-单细胞原体,从而改变了LSC的起源.
- 发生RAS突变的LSCs表现出BCL2家族基因表达的改变,从而产生对venetoclax的耐药性,并导致单细胞AML,治疗结果不佳.
结论:
- RAS突变通过限制LSC目标细胞来塑造AML的非遗传细胞层次.
- 在AML患者中,RAS驱动的LSC变化有助于静脉抗和单细胞复发.
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