Targeting methyltransferase PRMT5 eliminates leukemia stem cells in chronic myelogenous leukemia
Targeting methyltransferase PRMT5 eliminates leukemia stem cells in chronic myelogenous leukemia
复制标题
靶向甲基转移酶 PRMT5 消除慢性粒细胞白血病中的白血病干细胞
DOI：
10.1172/jci85239
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发表时间：
2016-10-01
影响因子：
15.9
通讯作者：
Pan, Jingxuan
中科院分区：
文献类型：
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作者：
Jin, Yanli;Zhou, Jingfeng;Pan, Jingxuan
伊马替尼不敏感的白血病干细胞 (LSC) 被认为是导致 BCR-ABL 酪氨酸激酶抑制剂耐药和慢性粒细胞白血病 (CML) 复发的原因。确定根除 CML LSC 的治疗靶点可能是治愈 CML 的一种策略。在本研究中，我们发现 CML 细胞中 BCR-ABL 和蛋白精氨酸甲基转移酶 5 (PRMT5) 之间存在正反馈环。在人类 CML LSC 中观察到 PRMT5 过度表达。使用 shRNA 沉默 PRMT5 或使用小分子抑制剂 PJ-68 阻断 PRMT5 甲基转移酶活性可降低 CML 患者 LSC 的存活率、连续重铺能力和长期培养起始细胞 (LTC-IC)。此外，PRMT5 敲低或 PJ-68 治疗可显着延长逆转录病毒 BCR-ABL 驱动的 CML 小鼠模型的存活率，并损害移植的 CML LSC 的体内自我更新能力。 PJ-68 还抑制免疫缺陷小鼠体内人类 CML CD34(+) 细胞的长期植入。此外，抑制PRMT5可通过消除disheveledhomolog 3 (DVL3)来消除CML CD34(+)细胞中的Wnt/β-连环蛋白通路。这项研究表明组蛋白精氨酸残基的表观遗传甲基化修饰是控制 LSC 自我更新的调节机制，并表明 PRMT5 可能是 LSC 的潜在治疗靶点。
lmatinib-insensitive leukemia stem cells (LSCs) are believed to be responsible for resistance to BCR-ABL tyrosine kinase inhibitors and relapse of chronic myelogenous leukemia (CML). Identifying therapeutic targets to eradicate CML LSCs may be a strategy to cure CML. In the present study, we discovered a positive feedback loop between BCR-ABL and protein arginine methyltransferase 5 (PRMT5) in CML cells. Overexpression of PRMT5 was observed in human CML LSCs. Silencing PRMT5 with shRNA or blocking PRMT5 methyltransferase activity with the small-molecule inhibitor PJ-68 reduced survival, serial replating capacity, and long-term culture-initiating cells (LTC-ICs) in LSCs from CML patients. Further, PRMT5 knockdown or PJ-68 treatment dramatically prolonged survival in a murine model of retroviral BCR-ABL-driven CML and impaired the in vivo self-renewal capacity of transplanted CML LSCs. PJ-68 also inhibited long-term engraftment of human CML CD34(+) cells in immunodeficient mice. Moreover, inhibition of PRMT5 abrogated the Wnt/beta-catenin pathway in CML CD34(+) cells by depleting dishevelled homolog 3 (DVL3). This study suggests that epigenetic methylation modification on histone protein arginine residues is a regulatory mechanism to control self-renewal of LSCs and indicates that PRMT5 may represent a potential therapeutic target against LSCs.