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诱导RIG-I的小分子通过点燃过载的dsRNA武器库,强烈抑制HMA耐性AML

Xueqin Chen¹, Jiaqi Wu¹, Yuntong Li¹

¹Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

Advanced science (Weinheim, Baden-Wurttemberg, Germany)

|June 26, 2025

概括

在急性髓性白血病 (AML) 中,通过重新触发干扰素 (IFN) 免疫反应来克服DNA低甲基化剂 (HMA) 的耐药性. 全跨网红酸 (ATRA) 和塔米巴洛 (TAM) 对抗HMA抗性AML细胞具有强大的选择性.

科学领域:

在瘤学瘤学.
免疫学免疫学免疫学
分子生物学分子生物学

背景情况:

DNA低甲基化剂 (HMA) 是急性骨髓性白血病 (AML) 和骨髓质综合征 (MDS) 的标准治疗方法.
大多数接受HMA治疗的患者最终会复发,面临有限的治疗选择.
一个关键的挑战是理解和克服HMA抵抗机制.

研究的目的:

确定新的治疗策略,以克服AML中的HMA耐药性.
阐明HMA耐药性背后的分子机制.
发现有选择性向和消除HMA耐药AML细胞的化合物.

主要方法:

高通量查以确定有效对抗HMA耐药AML细胞的化合物.
研究内源性病毒双链RNA (dsRNA) 和视网膜酸诱导基因I (RIG-I) 在HMA耐药性中的作用.
在AML细胞系,异种移植小鼠模型和患者衍生原始细胞中评估已识别的化合物的疗效.
一个针对RIG-I.的复合库的合理构建和选.

主要成果:

全跨网红酸 (ATRA) 被确定为HMA耐药AML细胞的选择性抑制剂.
抗HMA与过载的dsRNA和下调的RIG-I有关,影响干扰素 (IFN) 免疫反应.
ATRA恢复RIG-I表达,重新触发IFN反应,并抑制耐药AML细胞.
已批准的AML药物塔米巴洛 (TAM) 通过诱导RIG-I.显示出对抗HMA抵抗细胞的高选择性和强度.
无论是ATRA还是TAM都没有选择性地抑制p53突变癌细胞.

结论:

在AML中HMA耐药性的常见机制涉及RIG-I介导的IFN免疫反应受损.
恢复RIG-I表达和IFN信号是一种克服HMA抵抗的可行策略.
ATRA和TAM是有力的和有选择性的药物,能够通过重新激活抗癌免疫反应来克服AML中的HMA耐药性.

关键词:

在RIG-I中,RIG-I是指RIG-I.急性骨髓性白血病 (AML) 是一种急性骨髓性白血病.对抗癌症的免疫反应.低甲化剂是一种低甲化剂.干扰子干扰子干扰子

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