多发性骨髓瘤（MM）目前仍不可治愈，具有复发难治的特征，一直是临床治疗的难题，而MM干细胞是导致耐药和复发的重要因素。人们逐渐认识到组蛋白赖氨酸甲基化修饰与MM的发病关系密切，然而其在维持MM干细胞中发挥的作用及调控机制尚不明确。我们的前期研究发现组蛋白赖氨酸甲基转移酶SMYD2在MM中存在高表达，SMYD2抑制剂对MM细胞株、MM患者原代细胞均具有抗肿瘤活性及诱导MM细胞发生凋亡；同时，SMYD2抑制剂对MM干细胞也具有抑制作用，表明SMYD2在调控MM细胞生长及MM干细胞存活中具有重要的功能。本课题拟进一步探讨SMYD2促进MM细胞生长及维持MM干细胞的作用及机制；通过特异性shRNA、过表达质粒及SMYD2抑制剂干预获得有力证据；建立动物模型明确SMYD2对体内肿瘤生长的影响；并与临床相结合，有望为消除MM干细胞与治疗MM提供新靶点，以及提供判断疾病进程与生存预后的新生物标志物。

Even though patients with multiple myeloma (MM) are highly responsive to a variety of anticancer agents, MM remains an incurable disease with current approaches because the majority of MM patients are prone to relapse and have refractory disease. The existence of cancer stem cells in MM is believed one of the crucial causes of MM drug resistance and relapse. Methylation modification at histone lysines plays a critical role in the carcinogenesis and progression of cancer, including MM. However, the effect of histone lysine methyltransferase in the maintenance of MM stem cells is not clear yet. Our preliminary data demonstrated that histone lysine methyltransferase SMYD2 was highly overexpressed in MM cell lines and primary cells from patients with MM. Moreover, SMYD2 inhibitor exerted antitumor activity in MM cell lines and primary MM cells, and also killed MM stem cells. These prompted us to raise the working hypothesis that SMYD2 may play a critically oncogenic role in regulating the proliferation of bulk and sustaining self-renewal of cancer stem cells in MM. This study aims to further explore the pro-proliferation effects of SMYD2 on MM cells and its function in maintaining MM stem cells; elucidate the underlying mechanisms; observe the effects of specific shRNA, overexpressed plasmid and SMYD2 inhibitor on MM cells and MM stem cells; confirm the oncogenic role of SMYD2 in vivo model and evaluate the prognostic significance of SMYD2. This project is anticipated to provide evidence that SMYD2 could be a novel therapeutic target for eliminating stem cells in MM.