靶向去泛素化蛋白酶USP2a在多发性骨髓瘤发病及治疗中的作用及其机制

Multiple myeloma (MM) is a plasma cell-derived hematological malignancy. Although the application of bortezomib, a proteasome inhibitor, has led to a qualitative leap in the overall survival of patients with MM, most patients are still inevitably suffering drug resistant or relapse. Recently, Applicants have found USP2a is significantly overexpressed in primary MM cells and MM cell lines, while knockdown of USP2a in MM cell line results in inhibition of MM cell growth, increase of apoptosis, and significantly inhibits its ability to grow on nude mice. We also screened out a small molecule inhibitor WW-1 can specifically target USP2a, inhibit the proliferation of a variety of MM cell lines and primary cells. Based on these important discoveries, we will investigate the role of USP2a in the development of MM by using the MM mouse model, develop novel USP2a inhibitors. These findings will provide insights into the pathogenesis of multiple myeloma, provide a novel USP2a targeting lead compounds , and a new opportunity for the treatment of multiple myeloma .

多发性骨髓瘤（MM）是浆细胞来源的血液系统恶性肿瘤。虽然蛋白酶体抑制剂-硼替佐米的应用使MM患者的总生存率有了质的飞跃，但大部分患者仍不可避免会出现耐药和复发。新近，课题申请人发现USP2a在原代MM细胞和细胞系中显著高表达，而敲除USP2a引起MM细胞生长抑制、凋亡增多,并显著抑制其在裸鼠上的成瘤能力。我们也初筛出的小分子抑制剂WW-1可以特异性靶向USP2a，对多种MM细胞系及原代细胞均有良好的抑制增殖，诱导凋亡效应等。本课题拟在这些重要发现的基础上，进一步利用MM小鼠模型明确USP2a在其发病中的作用和机制，并以USP2a为靶点发展USP2a特异性抑制剂。这些研究成果将为多发性骨髓瘤的发病机制提供新的见解，为其治疗提供新的靶标和先导化合物，对多发性骨髓瘤的治疗提供新的契机。

多发性骨髓瘤（MM）是浆细胞来源的血液系统恶性肿瘤。虽然不断涌现的新药MM患者的总生存率有了质的飞跃，但大部分患者仍不可避免会出现耐药和复发。课题申请人发现去泛素化酶USP2a在原代MM细胞和细胞系中显著高表达，是治疗MM的潜在靶点，也初筛出的小分子抑制剂WW-1可以特异性靶向USP2a，对多种MM细胞系及原代细胞均有良好的抑制增殖，诱导凋亡效应等。USP2a在MM细胞中可通过RAS/ERK和STAT5信号通路激活上调；Usp2a基因敲除显著抑制小鼠MM的发生发展；WW-1TKI对MM细胞系及原代MM细胞均具有较好的杀伤作用，并降低原代MM细胞的集落形成。WW-1的使用也显著提高了MM小鼠的存活时间。综上所述，靶向USP2a是治疗MM的新策略。