Gleevec耐药是当前制约慢性粒细胞性白血病（CML）治愈的瓶颈，而白血病干细胞（LSC）是导致其耐药的重要因素。目前对于维持LSC 自我更新的信号通路还知之甚少。我们的前期工作证明蛋白质精氨酸甲基化转移酶PRMT5与Bcr-Abl表达呈正反馈相互调节，PRMT5促进LSC增殖，本课题拟进一步在病人LSC阐明PRMT5与Bcr-Abl正反馈相互调节的内在关系；揭示PRMT5促进LSC自我更新引起Gleevec耐药的机制；通过特异性shRNA或我们团队合成的PRMT5特异性小分子抑制剂PJ-T54干预，分别从CML原代细胞和小鼠模型观察特异性抑制PRMT5对CML LSC的杀伤效应。通过上述研究揭示PRMT5作为调控CML LSC的新信号通路分子，同时为清除CML LSC找到一种新靶向治疗先导化合物PJ-T54。本课题的重要性还在于发现肿瘤干细胞干性受蛋白质精氨酸甲基化修饰的调节。

Gleevec has reached great success in treating patients with chronic myelogenous leukemia (CML), but resistance to Gleevec is now an emerging problem. Among the factors to confer resistance to Gleevec is leukemia stem cells (LSC). The signaling pathway for maintaining LSC self-renewal is poorly understood. We discovered a positive feedback loop between protein arginine methyltransferase 5 (PRMT5) and Bcr-Abl in CML cells, and PRMT5 promote the proliferation of LSC. This study is aimed at clarifying the relationship between PRMT5 and Bcr-Abl in primary LSC; elucidate the underlying mechanism of PRMT5 conferring resistance to Gleevec by promoting self-renewal of LSC; observe the effect of specific shRNA or synthesized PRMT5 small-molecule inhibitor PJ-T54 on CML LSC in vitro and in CML mice model. The study will reveal PRMT5 as a new signaling pathway member regulating CML LSC and find a new lead compound PJ-T54 that is capable of killing CML LSC. This project is anticipated to elucidate that cancer stem cells are regulated by protein arginine methylation, which will extend our understanding the epigenetic regulation of cancer stem cells is not only through protein acetylation.