2. Academic Validation
  3. RIG-I-Inducing Small Molecules Potently Inhibit HMA-Resistant AML Through Igniting the Overloaded dsRNA Arsenal

RIG-I-Inducing Small Molecules Potently Inhibit HMA-Resistant AML Through Igniting the Overloaded dsRNA Arsenal

  • Adv Sci (Weinh). 2025 Jun 26:e14477. doi: 10.1002/advs.202414477.
Xueqin Chen 1,  Jiaqi Wu 1,  Yuntong Li 1,  Jiayu Huang 1,  Xiangqin Weng 1,  Jiale Wu 1,  Shujun Xiao 1 2,  Huaxin Song 1,  Zhengyuan Wang 1,  Ni Yan 1,  Fangfang Shi 1,  Derun Zheng 1 2,  Kai Tan 1 2,  Hesong Zhang 1,  Jingyi Cui 1 2,  Wen Wu 1,  Wei Wu 3,  Sujiang Zhang 1,  Min Lu 1
Affiliations

Affiliations

  • 1 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.
  • 2 School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 3 Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China.
PMID: 40568903 DOI: 10.1002/advs.202414477
Abstract

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 IC50 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.

Keywords

RIG‐I; acute myeloid leukemia; anticancer immune response; hypomethylating agent; interferon.

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