Rapsyn介导的CML干细胞中BCR-ABL ufmylation修饰及其干预策略

白血病干细胞（LSC）的存在是慢性粒细胞白血病（CML）患者对BCR-ABL激酶抑制剂耐受及疾病复发的根本原因，寻找针对 LSC的新靶点是治愈CML的关键。本课题组前期发现小分子化合物TGI-1002除通过抑制SET-PP2A相互作用发挥抗伊马替尼耐药CML细胞增殖外，还与Rapsyn存在特异性结合。近期又发现Rapsyn在CML细胞株及CML病人外周血中高度表达，还作为E3连接酶介导BCR-ABL的ufmylation修饰，提示其可能与白血病细胞干性维持及CML的发生发展密切相关。本课题将通过研究Rapsyn E3连接酶直接调控BCR-ABL ufmylation修饰的分子机制、考察BCR-ABL ufmylation修饰与泛素化降解间的关系以及对LSC中相关信号通路及“干性”维持的影响，较完整地揭示TGI-1002抗CML的新颖作用机制，为清除白血病干细胞提供新的依据和策略。

Leukemia stem cells (LSC) are believed to be the basic reason for resistance to BCR-ABL tyrosine kinase inhibitors and relapse of chronic myelogenous leukemia (CML). Identifying therapeutic targets to eradicate CML LSC could be a new strategy to cure CML. Our previous study showed that TGI1002, a small molecule overcame BCR-ABL mutation of CML through binding to oncoprotein SET, also bound acetylcholine receptor-associated protein (Rapsyn). Based on recently reported E3 ligase activity of Rapsyn, we discovered for the first time that Rapsyn was aberrantly overexpressed in CML cell lines and the blood of CML patients, and it could serve as an E3 ligase to mediate BCR-ABL ufmylation, indicating a close relationship between BCR-ABL ufmylation and the development of CML. In the present study, we will elucidate the molecular mechanism of Rapsyn as an E3 ligase for BCR-ABL ufmylation, explore the effects of BCR-ABL ufmylation on the stability of BCR-ABL, the survival pathways and maintenance of CML LSC. Meanwhile, we will also examine the effects of TGI1002 on the expression of Rapsyn, BCR-ABL ufmylation, the proliferation and functions of CML LSC in cell lines and animal models. The present study will provide a new target and strategy to ultimately eradicate CML.