The role of RAS mutations in leukemia progression, differentiation, and drug resistance

IF 0.8 Q4 HEMATOLOGY

Leukemia Research Reports Pub Date : 2026-01-01 Epub Date: 2026-04-11 DOI:10.1016/j.lrr.2026.100589

Congfa Jiang , Hangxuan Wang , Jiaxin Zhao , Yuwei Xu , Shiwei Duan

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Abstract

Mutations in the RAS gene family (NRAS, KRAS) are critical drivers of late-stage acute myeloid leukemia (AML) progression. They are frequently detected in relapsed/refractory AML and AML transformed from myelodysplastic syndrome (MDS). Occurring as late-stage genetic events, RAS mutations synergize with early drivers to promote leukemogenesis. While mutually exclusive with FLT3-ITD mutations, they coexist with KIT, RUNX1, CEBPA mutations and MLL rearrangements. Granulocyte-monocyte progenitors (GMPs) serve as the cellular origin for RAS-mutant leukemia stem cells (LSCs). Ultimately, RAS mutations drive monocytic differentiation of LSCs and venetoclax (VEN) resistance through BCL-2 family rewiring. Beyond AML, they are hallmark genetic lesions in juvenile myelomonocytic leukemia (JMML) and present in 15%-20% of pediatric acute lymphoblastic leukemia (ALL) cases. Here, we propose a comprehensive pathogenic model and targeted therapeutic framework focusing on RAS, MCL-1, BCL2L1 to overcome drug resistance and improve patient outcomes.

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RAS突变在白血病进展、分化和耐药性中的作用

RAS基因家族（NRAS， KRAS）的突变是晚期急性髓性白血病（AML）进展的关键驱动因素。它们经常在复发/难治性AML和骨髓增生异常综合征（MDS）转化的AML中检测到。RAS突变作为晚期遗传事件发生，与早期驱动因素协同作用，促进白血病发生。虽然它们与FLT3-ITD突变互斥，但它们与KIT、RUNX1、CEBPA突变和MLL重排共存。粒细胞-单核细胞祖细胞（GMPs）是ras突变白血病干细胞（LSCs）的细胞来源。最终，RAS突变通过BCL-2家族重新布线驱动LSCs的单核细胞分化和ventoclax （VEN）抗性。除AML外，它们是青少年髓单细胞白血病（JMML）的标志性遗传病变，在15%-20%的儿童急性淋巴细胞白血病（ALL）病例中存在。在此，我们提出了一个以RAS、MCL-1、BCL2L1为中心的综合致病模型和靶向治疗框架，以克服耐药性并改善患者预后。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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