Yu Pei-Han, Zhu Chen-Ying, Kang Yuan-Yuan, Naranmandura Hua, Yang Chang
Department of Hematology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
Department of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
Research (Wash D C). 2025 May 6;8:0696. doi: 10.34133/research.0696. eCollection 2025.
Arsenic trioxide (ATO) is able to selectively target and degrade the disease-causing PML::RARα (P/R) oncoprotein in acute promyelocytic leukemia (APL) for curing the disease. However, some relapsed patients develop resistance to ATO due to mutations in the promyelocytic leukemia (PML) part of the fusion gene. A relapsed APL patient had shown resistance to ATO and chemotherapy and was identified to harbor a point mutation (A216V) in the unrearranged allele rather than the fusion gene. Here, we report that mutations in the unrearranged allele impede the ATO-induced destabilization and degradation of the wild-type P/R oncoprotein. Deletion of the coiled-coil domain in a PML mutant completely reversed wild-type P/R protein resistance to ATO by abolishing the interaction between PML and P/R proteins. Collectively, our findings reveal that a point mutation in the unrearranged allele can confer ATO resistance through a protein-protein interaction. Therefore, the unrearranged allele should also be screened for drug-resistant mutations in relapsed APL patients.
三氧化二砷（ATO）能够在急性早幼粒细胞白血病（APL）中选择性地靶向并降解致病的早幼粒细胞白血病/维甲酸受体α（PML::RARα，P/R）癌蛋白，从而治愈该疾病。然而，一些复发患者由于融合基因中早幼粒细胞白血病（PML）部分的突变而对ATO产生耐药性。一名复发的APL患者对ATO和化疗均表现出耐药性，经鉴定其未重排等位基因而非融合基因中存在一个点突变（A216V）。在此，我们报告未重排等位基因中的突变会阻碍ATO诱导的野生型P/R癌蛋白的去稳定化和降解。在PML突变体中缺失卷曲螺旋结构域，通过消除PML与P/R蛋白之间的相互作用，完全逆转了野生型P/R蛋白对ATO的耐药性。总体而言，我们的研究结果表明，未重排等位基因中的一个点突变可通过蛋白质-蛋白质相互作用赋予对ATO的耐药性。因此，对于复发的APL患者，也应筛查未重排等位基因中的耐药突变。
