Targeting PRMT9-mediated arginine methylation suppresses cancer stem cell maintenance and elicits cGAS-mediated anticancer immunity PMID: 38413714

ADC Targets in Oncology

2026-04-10

Targeting PRMT9-mediated arginine methylation suppresses cancer stem cell maintenance and elicits cGAS-mediated anticancer immunity

Nat Cancer. 2024 Apr;5(4):601-624. doi: 10.1038/s43018-024-00736-x.

Haojie Dong ^# ¹ , Xin He ^# ¹ , Lei Zhang ^# ¹ , Wei Chen ² , Yi-Chun Lin ³ , Song-Bai Liu ⁴ , Huafeng Wang ⁵ , Le Xuan Truong Nguyen ¹ , Min Li ⁶ , Yinghui Zhu ¹ , Dandan Zhao ¹ , Lucy Ghoda ¹ , Jonathan Serody ⁷ ⁸ , Benjamin Vincent ⁷ ⁹ , Leo Luznik ¹⁰ , Ivana Gojo ¹⁰ , Joshua Zeidner ⁷ , Rui Su ¹¹ , Jianjun Chen ¹¹ , Ritin Sharma ¹² ¹³ , Patrick Pirrotte ¹² ¹³ , Xiwei Wu ² ¹⁴ , Weidong Hu ¹⁵ , Weidong Han ¹⁶ , Binghui Shen ¹⁷ , Ya-Huei Kuo ¹ , Jie Jin ⁵ , Amandeep Salhotra ¹⁸ , Jeffrey Wang ³ , Guido Marcucci ¹ ¹⁸ , Yun Lyna Luo ³ , Ling Li ¹⁹ ²⁰

Affiliations

1. Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA.
2. Integrative Genomics Core, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA.
3. Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA.
4. Suzhou Key Laboratory of Medical Biotechnology, Suzhou Vocational Health College, Suzhou, People's Republic of China.
5. Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
6. Division of Biostatistics, Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA.
7. Department of Medicine, Division of Hematology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
8. Department of Microbiology and Immunology and Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
9. Department of Microbiology and Immunology, Computational Medicine Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
10. Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
11. Department of Systems Biology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA.
12. Cancer & Cell Biology Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.
13. Integrated Mass Spectrometry Shared Resource, City of Hope Medical Center, Duarte, CA, USA.
14. Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA.
15. Department of Immunology and Theranostics, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA.
16. Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, People's Republic of China.
17. Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA.
18. Department of Hematology and HCT, City of Hope Medical Center, Duarte, CA, USA.
19. Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA. [email protected].
20. Department of Pediatrics, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA. [email protected].
# Contributed equally.

Abstract

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.