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

This study revolves around the protein arginine methyltransferase PRMT9, revealing its important role in acute myeloid leukemia (AML) and its potential as an anticancer target. Researchers found that PRMT9 expression levels were significantly elevated in AML stem cells and leukemic cells. Through gene editing and chemical probes, they discovered that inhibiting PRMT9 not only suppressed cancer cell survival but also induced DNA damage and cell cycle arrest in cancer cells, activated the intracellular cGAS-STING signaling pathway, thereby triggering type I interferon responses, activating dendritic cells, and stimulating T cell immunity.

This study was jointly conducted by Dr. Ling Li from Johns Hopkins University and her collaborators, with the findings published in the April 2024 issue of Nature-Cancer.

Details of the study are as follows:

1. Introduction to the research background Researchers noted that although current anticancer therapies can kill most cancer cells, it is still difficult to completely cure the disease, as cancer cells may hijack normal arginine methylation processes through unknown mechanisms to promote their survival. PRMT9 is a less-studied arginine methyltransferase whose activity is associated with various cancers.

2. Research methods and workflow The researchers first analyzed the expression levels of PRMT9 in leukemic and normal stem cells, finding it significantly upregulated in AML stem cells. They then constructed a conditional PRMT9 knockout mouse model through gene editing to study the role of PRMT9 in normal hematopoiesis and leukemogenesis.

To explore potential PRMT9 inhibitors, the researchers performed virtual screening and identified a small molecule compound, LD2, from 960,000 compounds that specifically inhibited the catalytic activity of PRMT9.

1. Main research findings In vitro and in vivo experiments showed that PRMT9 deficiency or treatment with the LD2 inhibitor significantly reduced the viability of AML cells, induced cell cycle arrest, and DNA damage. Mechanistic studies found that PRMT9 inhibition led to decreased arginine methylation levels of its downstream substrate XRN2, triggering DNA damage and activation of the intracellular cGAS kinase, producing STING agonists such as cGAMP, and stimulating type I interferon responses.

In mouse leukemia models, PRMT9 knockdown or LD2 treatment significantly prolonged mouse survival. Single-cell transcriptomic analysis showed that PRMT9 inhibition activated dendritic cells and cytotoxic T lymphocytes while reducing the proportion of regulatory T cells, thereby inducing a potent antitumor immune response. Further studies revealed that this anticancer immune effect was dependent on the activation of the cGAS-STING pathway induced by PRMT9 inhibition.

1. Research significance This study unraveled the crucial role of PRMT9 in the development of AML and provided a new potential target for precision treatment of AML. Moreover, this work discovered that PRMT9 inhibitors could elicit host antitumor immunity through the cGAS-STING pathway and synergize with PD-1 inhibitors, opening new avenues for immunotherapy of AML.

This is a highly innovative and valuable study that not only elucidates the molecular mechanisms of PRMT9 in tumorigenesis and immune evasion but also develops a small molecule PRMT9 inhibitor, bringing new hope for the clinical treatment of leukemia.