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Updated: Jul 2, 2025

Exploring the Arginine Methylome by Nuclear Magnetic Resonance Spectroscopy
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Exploring the Arginine Methylome by Nuclear Magnetic Resonance Spectroscopy

Published on: December 16, 2021

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

Haojie Dong1, Xin He1, Lei Zhang1

  • 1Department 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.

Nature Cancer
|February 27, 2024
PubMed

Insights

Targeting protein arginine N-methyltransferase 9 (PRMT9) in acute myeloid leukemia (AML) eliminates cancer cells by disrupting their survival mechanisms and activating anti-cancer immunity. This novel strategy shows promise for treating AML and other cancers.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Immunology

Background:

  • Current cancer therapies are limited in their ability to eradicate all cancer cells.
  • Cancer cells exploit normal cellular processes, such as arginine methylation, for their survival and maintenance.
  • The precise mechanisms by which cancer cells utilize arginine methylation remain largely unknown.

Purpose of the Study:

  • To investigate the role of protein arginine N-methyltransferase 9 (PRMT9) in acute myeloid leukemia (AML) pathogenesis.
  • To determine if targeting PRMT9 can serve as a therapeutic strategy for AML.
  • To elucidate the mechanisms by which PRMT9 contributes to cancer cell survival and immune evasion.

Main Methods:

  • Assessed PRMT9 activity in leukemia cells and stem cells from AML patients.
  • Utilized PRMT9 ablation and inhibition in AML models.
  • Analyzed the impact of PRMT9 targeting on RNA translation, DNA damage response, and type I interferon (IFN) signaling.
  • Investigated the synergistic effects of PRMT9 inhibitors with anti-programmed cell death protein 1 (anti-PD-1) therapy.

Main Results:

  • PRMT9 activity was elevated in AML blasts and leukemia stem cells (LSCs).
  • PRMT9 ablation in AML cells reduced arginine methylation of key survival regulators, leading to decreased cell survival.
  • PRMT9 inhibition induced DNA damage and activated cyclic GMP-AMP synthase (cGAS), a key mediator of type I IFN responses.
  • Genetic activation of cGAS in AML cells inhibited leukemogenesis, and PRMT9 inhibition showed synergy with anti-PD-1 therapy in eradicating AML.

Conclusions:

  • PRMT9 plays a critical role in the survival and immune evasion of both LSCs and non-LSCs in AML.
  • Targeting PRMT9 disrupts cancer cell maintenance through intrinsic mechanisms and enhances anti-cancer immunity via type I IFN pathways.
  • PRMT9 inhibition represents a promising therapeutic strategy for AML, potentially in combination with immunotherapy.

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