Blockade of deubiquitinase YOD1 degrades oncogenic PML/RARα and eradicates acute promyelocytic leukemia cells

In most acute promyelocytic leukemia (APL) cells, promyelocytic leukemia (PML) fuses to retinoic acid receptor alpha (RAR alpha) due to chromosomal translocation, thus generating PML/RAR alpha oncoprotein, which is a relatively stable oncoprotein for degradation in APL. Elucidating the mechanism regulating the stability of PML/RAR alpha may help to degrade PML/RAR alpha and eradicate APL cells. Here, we describe a deubiquitinase (DUB)-involved regulatory mechanism for the maintenance of PML/RAR alpha stability and develop a novel pharmacological approach to degrading PML/RAR alpha by inhibiting DUB. We utilized a DUB siRNA library to identify the ovarian tumor protease (OTU) family member deubiquitinase YOD1 as a critical DUB of PML/RAR alpha. Suppression of YOD1 promoted the degradation of PML/RAR alpha, thus inhibiting APL cells and prolonging the survival time of APL cell-bearing mice. Subsequent phenotypic screening of small molecules allowed us to identify ubiquitin isopeptidase inhibitor I (G5) as the first YOD1 pharmacological inhibitor. As expected, G5 notably degraded PML/RAR alpha protein and eradicated APL, particularly drug-resistant APL cells. Importantly, G5 also showed a strong killing effect on primary patient-derived APL blasts. Overall, our study not only reveals the DUB-involved regulatory mechanism on PML/RAR alpha stability and validates YOD1 as a potential therapeutic target for APL, but also identifies G5 as a YOD1 inhibitor and a promising candidate for APL, particularly drug-resistant APL treatment. (C) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

Automated summary

This study reveals a DUB-involved mechanism in regulating the stability of PML/RARα and develops a novel pharmacological approach to degrade PML/RARα by inhibiting DUB. The key DUB involved in this mechanism is identified as ovarian tumor protease YOD1. Inhibition of YOD1 promotes the degradation of PML/RARα and effectively inhibits the growth of APL cells.