USP47 Is a New Target in Chronic Myelogenous Leukemia

Abstract Despite of the great success of tyrosine kinase inhibitor in the therapy of chronic myelogenous leukemia (CML), CML is still not curable. Further investigation on the molecular mechanism of CML pathogenesis and identification of novel therapeutic target are required. In this study, we found that overexpression of CML characterized Bcr/Abl oncoprotein could significantly upregulate the expression of ubiquitin-specific protease Usp47. Also, increased expression of Usp47 was observed in primary CML cells and its expression was associated with the treatment response of imatinib, the first generation of tyrosine kinase inhibitor. Furthermore, Usp47 knockdown could inhibit the proliferation of K562 cells in vitro and in vivo. P22077, a Usp47 inhibitor, could inhibit the proliferation of CML cell lines, which comprise BCR/ABL mutation, including the T315I mutation. P22077 inhibits the proliferation of primary CML cells sensitive or resistant to imatinib. The colony forming activity of CD34+ from CML primary cells but not from normal cord blood cells were also inhibited by P22077. We further demonstrated that inactivation of STAT5 significantly reduce the expression of Usp47, indicating that BCR/ABL-induced upregulation of Usp47 is mediated by STAT5 activition. Interestingly, Usp47 could interact with Sirt1, another STAT5 target gene. Inactivation of Usp47 reduces the expression of Sirt1 in CML cell lines and primary CML cells. Taken together, we demonstrated that Usp47 plays an critical role in CML, revealing a novel BCR/ABL/STAT5/Usp47/Sirt1 signaling pathway in CML, providing a potential target to overcome tyrosine kinase inhibitor resistance. Disclosures No relevant conflicts of interest to declare.