Current anticancer therapies cannot eliminate all cancer cells, which hijack normal arginine methylation as a means to promote their maintenance via unknown mechanisms. Here we show that targeting protein arginine N-methyltransferase 9 (PRMT9), whose activities are elevated in blasts and leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML), eliminates disease via cancer-intrinsic mechanisms and cancer-extrinsic type I interferon (IFN)-associated immunity. PRMT9 ablation in AML cells decreased the arginine methylation of regulators of RNA translation and the DNA damage response, suppressing cell survival. Notably, PRMT9 inhibition promoted DNA damage and activated cyclic GMP-AMP synthase, which underlies the type I IFN response. Genetically activating cyclic GMP-AMP synthase in AML cells blocked leukemogenesis. We also report synergy of a PRMT9 inhibitor with anti-programmed cell death protein 1 in eradicating AML. Overall, we conclude that PRMT9 functions in survival and immune evasion of both LSCs and non-LSCs; targeting PRMT9 may represent a potential anticancer strategy.

目前的抗癌疗法无法消除所有癌细胞，它们劫持正常的精氨酸甲基化，作为通过未知机制促进其维持的手段。在这里，我们发现，靶向蛋白精氨酸N-甲基转移酶 9 (PRMT9) 在急性髓性白血病 (AML) 患者的原始细胞和白血病干细胞 (LSC) 中活性升高，可通过癌症内在机制和癌症外在类型消除疾病I 干扰素 (IFN) 相关免疫。AML 细胞中 PRMT9 的消除降低了 RNA 翻译调节因子的精氨酸甲基化和 DNA 损伤反应，从而抑制细胞存活。值得注意的是，PRMT9 抑制促进了 DNA 损伤并激活了环 GMP-AMP 合酶，这是 I 型 IFN 反应的基础。基因激活 AML 细胞中的环 GMP-AMP 合酶可阻止白血病发生。我们还报告了 PRMT9 抑制剂与抗程序性细胞死亡蛋白 1 在根除 AML 方面的协同作用。总体而言，我们得出结论，PRMT9 在 LSC 和非 LSC 的生存和免疫逃避中发挥作用；靶向 PRMT9 可能代表一种潜在的抗癌策略。