慢性粒细胞性白血病(CML)临床治疗遇到的主要挑战是imatinib耐药和疾病复发，而白血病干细胞(LSCs)的存在是耐药与复发的重要根源。LSCs自我更新的调控机制仍不清楚。前期研究发现蛋白赖氨酸甲基转移酶SMYD3在CML LSCs(CD34+ CD38-)中高表达，沉默其表达可诱导 LSCs凋亡、抑制CML LSCs的连续集落形成能力。基于这些结果，我们提出工作假设：SMYD3在维持CML LSCs自我更新和存活中发挥重要作用。本课题旨在验证这一假设，进一步系统阐明SMYD3维持CML LSCs自我更新引起imatinib耐药的关键作用；分别在病人原代细胞和CML小鼠模型明确SMYD3基因沉默对CML LSCs的清除作用；揭示SMYD3调控CML LSCs自我更新的分子机制。通过上述研究，预期确认SMYD3作为CML LSCs精准干预的新靶点，提升对LSCs自我更新调控机制的认识。

Imatinib resistance and disease relapse are among the major challenges for the treatment of patients with chronic myelogenous leukemia (CML). Quiescent leukemia stem cells (LSCs) insensitive to imatinib offer seeds for such resistance and relapse. The signaling pathways for sustaining self-renewal capacity of LSCs are poorly understood. Our preliminary data revealed that protein lysine methyltransferase SMYD3 was selectively overexpressed in human CML LSCs (CD34+ CD38-). Silencing SMYD3 by a specific shRNA induced apoptosis of quiescent CML LSCs and reduced long-term serial colony-forming cell (CFC) replating in methylcellulose medium of CD34+ cells. These findings prompted us to hypothesize that SMYD3 might play a critical role in maintaining the self-renewal and survival capacity of CML LSCs. The present study is aimed to test this hypothesis and elucidate the underlying mechanism that SMYD3 promotes the self-renewal of CML LSCs to confer imatinib resistance; observe the elimination effect of specific SMYD3 shRNA on LSCs in patient samples and CML mice model. Taken together, this study will hopefully shed a light on the understanding of LSCs regulation and validate SMYD3 as therapeutic target to eliminate LSCs.