Targeting Arginine Methylation Suppresses Cancer Stem Cell Maintenance and Elicits cGAS-mediated anti-Cancer Immunity II. Targeting Arginine Methylation Suppresses Cancer Stem Cell Maintenance and Elicits cGAS-mediated anti-Cancer Immunity II

Current anti-cancer therapies cannot eliminate all the cancer cells, which hijack normal arginine methylation as a means to promote their own maintenance via unknown mechanisms. Herein, we show that targeting protein arginine methyltransferase 9 (PRMT9), whose activities are elevated in leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML), eliminates disease via cancer-intrinsic mechanisms and cancer-extrinsic Type-I Interferon (IFN-I)-associated immunity. PRMT9 ablation in AML cells decreased arginine methylation of regulators of RNA translation and the DNA damage response, suppressing cell survival. Notably, PRMT9 inhibition promoted DNA damage and activated cGAS, which underlies the IFN-I response. Genetically activating cGAS in AML cells blocked leukemogenesis. We also report synergy of a PRMT9 inhibitor with anti-PD1 in eradicating PRMT9-proficient cancers, including AML and lymphoma. We conclude that PRMT9 governs LSCs survival and immune evasion, and that combining a PRMT9 inhibitor with an immune checkpoint inhibitor represents a novel anti-cancer strategy. Overall design: BM cells in MA9 transplanted mice were collected for analysis.

当前的抗癌疗法无法彻底清除全部癌细胞，癌细胞会劫持正常的精氨酸甲基化过程，通过尚未阐明的分子机制维持自身存活。本研究证实，靶向蛋白精氨酸甲基转移酶9（protein arginine methyltransferase 9, PRMT9）——其在急性髓系白血病（acute myeloid leukemia, AML）患者的白血病干细胞（leukemia stem cells, LSCs）中活性上调——可通过癌细胞内在机制以及癌细胞外在的I型干扰素（Type-I Interferon, IFN-I）相关免疫应答清除疾病病灶。在AML细胞中敲除PRMT9，会降低RNA翻译调控因子与DNA损伤应答因子的精氨酸甲基化水平，进而抑制细胞存活。值得注意的是，抑制PRMT9可诱发DNA损伤并激活cGAS，而这正是IFN-I应答的分子基础。在AML细胞中通过遗传学手段激活cGAS，能够阻断白血病发生进程。本研究还发现，PRMT9抑制剂与抗PD-1（anti-PD1）抗体联合使用，可彻底清除表达PRMT9的恶性肿瘤，包括AML与淋巴瘤。本研究结论表明，PRMT9调控白血病干细胞的存活与免疫逃逸，而将PRMT9抑制剂与免疫检查点抑制剂联合使用，有望成为一种全新的抗癌治疗策略。实验整体设计：收集经MA9移植的小鼠体内的骨髓（bone marrow, BM）细胞用于后续分析。