近年来的研究发现，多种泛素化特异蛋白酶（USPs）分子与肿瘤的发生和发展密切相关，可望成为肿瘤治疗的新的靶点。最近，我们研究发现USP家族成员—USP47在慢性粒细胞白血病（CML）细胞中高表达，并且其表达水平和CML患者对酪氨酸激酶抑制剂的疗效密切相关；CML相关融合蛋白BCR/ABL显著上调USP47的表达，而利用小分子干扰RNA或小分子抑制化合物抑制USP47可在体内、外显著抑制CML细胞增殖，抑制原代CML CD34+细胞的克隆形成能力。本项目拟在这些重要发现的基础上，进一步应用USP47基因敲除小鼠模型，在分子、细胞和整体动物水平上研究USP47在CML发病和治疗中的作用和机制，尤其是对CML白血病干细胞的作用，可望为CML的发病机制研究提供新的见解，并为其治疗提供新的靶标和先导化合物，为研发治疗CML的新策略提供重要基础。

Ubiquitin specific proteases (USP) play an important role in regulating many cellular processes including cell cycle, signal transduction, immune response and DNA repair. Recently, it has been shown that many USP are closely associated with the development of cancer. And USP is becoming an attactive cancer targets. In this project, we found that USP47 expressed at higher level in CML bone marrow mononuclear cells than their normal counterpart. The expression of USP47 is changed with the treatment of tyrosine kinase inhibitor imatinib. Imatinib treatment resulted in the decrease of USP47. However, when the relapse occurred, the expression of USP47 were upregulated again. BCR/ABL, the driver force of CML, could significantly upregulate the expression of USP47. When the expression or the activity of USP47 was inhibited by RNA interference or by USP47 inhibitor, the proliferation and tumor formation of K562 cells were greatly reduced in vitro and in vivo. USP47 inhibitor could also inhibit the proliferation of primary CML cells and the colony formation of CML CD34+ cells. Based on these findings, we will next investigate the role of USP47 in the development of CML using the USP47 knockout mice as a mouse model, identify the interaction protein of USP47 from K562 cells with immunoprecipitation and mass spectrometry analysis, elucidate how BCR/ABL upregulates the expression of USP47 and identify novel USP47 inhibitors. These studies may shed new light on the pathogenesis of CML, provide novel drug target and novel USP47 targeting lead compounds for the treatment of CML.