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.

我们小组之前曾报道过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，这些成员参与表观遗传调控。在这里，我们探讨了 PRMT7 在维持慢性粒细胞白血病 (CML) 中的白血病干细胞 (LSC) 中的作用，因为它在 PRMT 家族中具有独特的功能。Prmt7 的遗传缺失以及PRMT7小分子特异性抑制剂的开发和测试表明，在 CML 小鼠模型和原发性 CML CD34 ⁺中，靶向 PRMT7 可延缓白血病发展和 LSC 自我更新受损来自人类的细胞而不影响正常的造血功能。从机制上讲，PRMT7 的缺失导致甘氨酸脱羧酶的表达减少，导致甘氨酸代谢重新编程以产生甲基乙二醛，这对 LSC 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 作为根除 CML 中 LSCs 的潜在治疗靶点。