Chen Xueqin, Wu Jiaqi, Li Yuntong, Huang Jiayu, Weng Xiangqin, Wu Jiale, Xiao Shujun, Song Huaxin, Wang Zhengyuan, Yan Ni, Shi Fangfang, Zheng Derun, Tan Kai, Zhang Hesong, Cui Jingyi, Wu Wen, Wu Wei, Zhang Sujiang, Lu Min
Shanghai 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.
School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.
Adv Sci (Weinh). 2025 Sep;12(36):e14477. doi: 10.1002/advs.202414477. Epub 2025 Jun 26.
DNA hypomethylating agents (HMAs) are widely used to treat acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS), but most treated patients relapse and lack standard treatment options. Using high-throughput screening, the approved all-trans retinoic acid (ATRA) is identified that exhibit high selectivity in killing HMA-resistant AML cells compared to parental cells. Mechanistically, HMA-resistant cells are overloaded with DNA hypomethylation-associated endogenous viral double-stranded RNA (dsRNA) which, however, fails to trigger an anticancer interferon (IFN) immune response due to downregulation of dsRNA sensor retinoic acid-inducible gene I (RIG-I). ATRA compensates for RIG-I expression, thereby re-triggering IFN response and potently inhibiting HMA-resistant AML cell lines, xenograft mice, and patient-derived primary cells. A library of potential RIG-I-inducing compounds is rationally constructed and screened, in which the approved M3 AML treatment drug tamibarotene (TAM) exhibits strikingly 28036-fold selectivity and 779 pm IC in killing HMA-resistant AML cells. ATRA and TAM do not selectively inhibit p53-mutant cancer cells. Together, this study uncovers a common resistance mechanism in HMA-treated AML patients and, in addition, provides highly potent and selective agents that can overcome resistance through re-triggering IFN anticancer immune response.
DNA低甲基化剂（HMAs）被广泛用于治疗急性髓系白血病（AML）/骨髓增生异常综合征（MDS），但大多数接受治疗的患者会复发，且缺乏标准治疗方案。通过高通量筛选，发现已获批的全反式维甲酸（ATRA）与亲代细胞相比，在杀死对HMA耐药的AML细胞方面具有高选择性。从机制上讲，对HMA耐药的细胞中DNA低甲基化相关的内源性病毒双链RNA（dsRNA）过载，然而，由于dsRNA传感器维甲酸诱导基因I（RIG-I）的下调，它未能触发抗癌干扰素（IFN）免疫反应。ATRA可补偿RIG-I的表达，从而重新触发IFN反应，并有效抑制对HMA耐药的AML细胞系、异种移植小鼠和患者来源的原代细胞。合理构建并筛选了一个潜在的RIG-I诱导化合物文库，其中已获批的M3 AML治疗药物他米巴罗汀（TAM）在杀死对HMA耐药的AML细胞方面表现出惊人的28036倍选择性和779 pm的半数抑制浓度（IC）。ATRA和TAM不会选择性抑制p53突变癌细胞。总之，本研究揭示了HMA治疗的AML患者中的一种常见耐药机制，此外，还提供了高效且选择性的药物，可通过重新触发IFN抗癌免疫反应来克服耐药性。
