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Targeting USP2 induces degradation of PML-RARα with or without drug-resistant mutations in acute promyelocytic leukemia

Zhang, J.; Wu, W.; Wang, Y.; Zhang, Y.; Wang, Y.; Bai, W.; Zhang, Z.; Zhu, C.; Wu, Y.; Zhang, Z.; Yang, L.; Lei, H.; Xu, H.; Zhou, L.; Wu, Y.

2025-05-14 cell biology
10.1101/2025.05.11.653221 bioRxiv
Show abstract

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-RAR and other factors. Here, it is demonstrated that inhibiting USP2 with ML364 or silencing USP2 reduces PML-RAR protein levels in both ATRA-sensitive and -resistant APL cells, an effect reversed by proteasome inhibition. Conversely, USP2 overexpression enhances PML-RAR stability. Mechanistically, USP2 interacts with and deubiquitinates PML-RAR, including drug-resistant mutants. Consistent with PML-RAR degradation, 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-RAR and highlights USP2 inhibition as a potential therapeutic strategy for APL with PML-RAR mutations.

Published in Acta Biochimica et Biophysica Sinica (predicted rank #2) · training set

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