In most acute promyelocytic leukemia(APL)cells,promyelocytic leukemia(PML)fuses to retinoic acid receptor α (RARα)due to chromosomal translocation,thus generating PML/RARαoncoprotein,which is a relatively stable on...In most acute promyelocytic leukemia(APL)cells,promyelocytic leukemia(PML)fuses to retinoic acid receptor α (RARα)due to chromosomal translocation,thus generating PML/RARαoncoprotein,which is a relatively stable oncoprotein for degradation in APL.Elucidating the mechanism regulating the stability of PML/RARαmay help to degrade PML/RARαand eradicate APL cells.Here,we describe a deubiquitinase(DUB)-involved regulatory mechanism for the maintenance of PML/RARαstability and develop a novel pharmacological approach to degrading PML/RARαby 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/RARα.Suppression of YOD1 promoted the degradation of PML/RARα,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/RARαprotein 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/RARαstability 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.展开更多
基金This work was supported by grants from the National Natural Science Foundation of China(No.81973354 to Meidan Ying)China Postdoctoral Science Foundation(No.2020T130593 to Xuejing Shao)Leading Talent of“Ten Thousand Plan”-National High-Level Talents Special Support Plan and the Fundamental Research Funds for the Central Universities(China).
文摘In most acute promyelocytic leukemia(APL)cells,promyelocytic leukemia(PML)fuses to retinoic acid receptor α (RARα)due to chromosomal translocation,thus generating PML/RARαoncoprotein,which is a relatively stable oncoprotein for degradation in APL.Elucidating the mechanism regulating the stability of PML/RARαmay help to degrade PML/RARαand eradicate APL cells.Here,we describe a deubiquitinase(DUB)-involved regulatory mechanism for the maintenance of PML/RARαstability and develop a novel pharmacological approach to degrading PML/RARαby 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/RARα.Suppression of YOD1 promoted the degradation of PML/RARα,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/RARαprotein 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/RARαstability 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.
