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

• USP2 is identified as a novel deubiquitinase for PML-RARα, regulating its stability. • Inhibition of USP2 with ML364 or silencing induces degradation of PML-RARα, including drug-resistant mutants. • USP2 inhibition triggers apoptosis in APL cell lines and primary leukemia cells. • Targeting USP2 represents a promising therapeutic strategy for APL, especially with PML-RARα mutations.