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Advanced Science

Advanced Science

IF: 14.3
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RIG-I-Inducing Small Molecules Potently Inhibit HMA-Resistant AML Through Igniting the Overloaded dsRNA Arsenal

Published:26 June 2025 DOI: 10.1002/advs.202414477 PMID: 40568903
Xueqin Chen, Jiaqi Wu, Yuntong Li, Jiayu Huang, Xiangqin Weng, Jiale Wu, Shujun Xiao, Huaxin Song, Zhengyuan Wang, Ni Yan, Fangfang Shi, Derun Zheng, Kai Tan, Hesong Zhang, Jingyi Cui, Wen Wu, Wei Wu, Sujiang Zhang, Min Lu

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.

Substances (30)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Retinoic acid 302-79-4 C20H28O2 985 suppliers $5.00-$5434.00
Retinoic acid 302-79-4 C20H28O2 985 suppliers $5.00-$5434.00
Retinoic acid 302-79-4 C20H28O2 985 suppliers $5.00-$5434.00
Retinoic acid 302-79-4 C20H28O2 985 suppliers $5.00-$5434.00
5-Azacytidine 320-67-2 C8H12N4O5 783 suppliers $7.00-$1767.15
5-Azacytidine 320-67-2 C8H12N4O5 783 suppliers $7.00-$1767.15
5-Azacytidine 320-67-2 C8H12N4O5 783 suppliers $7.00-$1767.15
5-Azacytidine 320-67-2 C8H12N4O5 783 suppliers $7.00-$1767.15
5-Aza-2'-deoxycytidine 2353-33-5 C8H12N4O4 727 suppliers $8.00-$2480.00
5-Aza-2'-deoxycytidine 2353-33-5 C8H12N4O4 727 suppliers $8.00-$2480.00
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