Targeting USP2 induces degradation of PML-RARαwith or without drug-resistant mutations in acute promyelocytic leukemiaOA
Despite the high efficacy of all-trans retinoic acid(ATRA)and arsenic trioxide(ATO)in treating acute promyelocytic leukemia(APL),approximately 10%-20%of patients develop drug resistance due to mutations in PML-RARαand other factors.Here,we find that inhibition of USP2 with ML364 or USP2 silencing reduces PML-RARαprotein levels in both ATRA-sensitive and ATRA-resistant APL cells,and this effect is reversed by proteasome inhibition.Conversely,USP2 overexpression enhances PML-RARαstability.Mechanistically,USP2 interacts with and deubiquitinates PML-RARα,including its drug-resistant mutants.Consistent with PML-RARαdegradation,ML364 treatment significantly induces apoptosis in APL cell lines and primary leukemia cells.In conclusion,this study identifies USP2 as a novel deubiquitinating enzyme for PML-RARαand highlights USP2 inhibition as a potential therapeutic strategy for APL with PML-RARαmutations.
Jie Zhang;Wenxuan Wu;Yun Wang;Youping Zhang;Yingying Wang;Wenhui Bai;Zhenge Zhang;Chujiao Zhu;Yunzhao Wu;Ziwei Zhang;Li Yang;Hu Lei;Hanzhang Xu;Li Zhou;Yingli Wu
Shanghai Institute of Hematology,State Key Laboratory of Medical Genomics,National Research Center for Translational Medicine at Shanghai,Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200025,ChinaHongqiao International Institute of Medicine,Shanghai Tongren Hospital/Faculty of Basic Medicine,Chemical Biology Division of Shanghai Universities E-Institutes,Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,ChinaShanghai Ruijin Rehabilitation Hospital,Shanghai 200023,ChinaHongqiao International Institute of Medicine,Shanghai Tongren Hospital/Faculty of Basic Medicine,Chemical Biology Division of Shanghai Universities E-Institutes,Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,ChinaHongqiao International Institute of Medicine,Shanghai Tongren Hospital/Faculty of Basic Medicine,Chemical Biology Division of Shanghai Universities E-Institutes,Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,ChinaHongqiao International Institute of Medicine,Shanghai Tongren Hospital/Faculty of Basic Medicine,Chemical Biology Division of Shanghai Universities E-Institutes,Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,ChinaHongqiao International Institute of Medicine,Shanghai Tongren Hospital/Faculty of Basic Medicine,Chemical Biology Division of Shanghai Universities E-Institutes,Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,ChinaHongqiao International Institute of Medicine,Shanghai Tongren Hospital/Faculty of Basic Medicine,Chemical Biology Division of Shanghai Universities E-Institutes,Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,ChinaYusuf Hamied Department of Chemistry,University of Cambridge,Cambridge CB21EW,UKYusuf Hamied Department of Chemistry,University of Cambridge,Cambridge CB21EW,UKHongqiao International Institute of Medicine,Shanghai Tongren Hospital/Faculty of Basic Medicine,Chemical Biology Division of Shanghai Universities E-Institutes,Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,ChinaHongqiao International Institute of Medicine,Shanghai Tongren Hospital/Faculty of Basic Medicine,Chemical Biology Division of Shanghai Universities E-Institutes,Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,ChinaHongqiao International Institute of Medicine,Shanghai Tongren Hospital/Faculty of Basic Medicine,Chemical Biology Division of Shanghai Universities E-Institutes,Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,ChinaShanghai Institute of Hematology,State Key Laboratory of Medical Genomics,National Research Center for Translational Medicine at Shanghai,Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200025,ChinaHongqiao International Institute of Medicine,Shanghai Tongren Hospital/Faculty of Basic Medicine,Chemical Biology Division of Shanghai Universities E-Institutes,Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China
医药卫生
acute promyelocytic leukemiaPML-RARαUSP2ML364drug resistance
《Acta Biochimica et Biophysica Sinica》 2026 (3)
P.574-583,10
supported by the grants from the National Natural Science Foundation of China(Nos.82470152,82170145,82170172)the CAMS Innovation Fund for Medical Sciences(No.2019-I2M-5-051)the Shanghai Municipal Commission of Health and Family Planning(No.ZY(2021-2023)-0208)the China Postdoctoral Science Foundation(No.2024M762019).
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