Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou 510632, China.
Department of Hematology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
Cell Metab. 2022 Jun 7;34(6):818-835.e7. doi: 10.1016/j.cmet.2022.04.004. Epub 2022 May 3.
Our group has reported previously on the role of various members of the protein arginine methyltransferase (PRMT) family, which are involved in epigenetic regulation, in the progression of leukemia. Here, we explored the role of PRMT7, given its unique function within the PRMT family, in the maintenance of leukemia stem cells (LSCs) in chronic myeloid leukemia (CML). Genetic loss of Prmt7, and the development and testing of a small-molecule specific inhibitor of PRMT7, showed that targeting PRMT7 delayed leukemia development and impaired self-renewal of LSCs in a CML mouse model and in primary CML CD34 cells from humans without affecting normal hematopoiesis. Mechanistically, loss of PRMT7 resulted in reduced expressions of glycine decarboxylase, leading to the reprograming of glycine metabolism to generate methylglyoxal, which is detrimental to LSCs. These findings link histone arginine methylation with glycine metabolism, while suggesting PRMT7 as a potential therapeutic target for the eradication of LSCs in CML.
我们的团队之前曾报道过参与表观遗传调控的蛋白质精氨酸甲基转移酶（PRMT）家族的各种成员在白血病进展中的作用。在这里，鉴于 PRMT7 在 PRMT 家族中的独特功能，我们探讨了 PRMT7 在慢性髓性白血病（CML）中的白血病干细胞（LSCs）维持中的作用。Prmt7 的遗传缺失，以及 PRMT7 的小分子特异性抑制剂的开发和测试表明，靶向 PRMT7 可延迟白血病的发展，并损害 CML 小鼠模型和来自人类的原发性 CML CD34 细胞中的 LSCs 的自我更新，而不会影响正常造血。从机制上讲，PRMT7 的缺失导致甘氨酸脱羧酶表达降低，导致甘氨酸代谢重新编程以产生甲基乙二醛，这对 LSCs 有害。这些发现将组蛋白精氨酸甲基化与甘氨酸代谢联系起来，同时表明 PRMT7 可能是消除 CML 中 LSCs 的潜在治疗靶标。
