# Therapeutic potential of PRMT1 as a critical survival dependency target in multiple myeloma

## TL;DR

This study identifies PRMT1 as a key survival target in multiple myeloma cells, suggesting that inhibiting PRMT1 could be a promising new treatment approach.

## Contribution

The study reveals PRMT1 as a novel survival dependency in multiple myeloma through a CRISPR screen and functional validation.

## Key findings

- PRMT1 inhibition with GSK3368715 reduces MM cell survival and alters arginine methylation patterns.
- PRMT1 inhibition causes cell cycle arrest and downregulates genes involved in proliferation and DNA damage response.
- Reduced levels of cell cycle and DDR proteins were observed following PRMT1 inhibition.

## Abstract

Multiple myeloma (MM) is a neoplasm of antibody-producing plasma cells and is the second most prevalent hematological malignancy worldwide. Development of drug resistance and disease relapse significantly impede the success of MM treatment, highlighting the critical need to discover novel therapeutic targets. In a custom CRISPR/Cas9 screen targeting 197 DNA damage response-related genes, Protein Arginine N-Methyltransferase 1 (PRMT1) emerged as a top hit, revealing it as a potential therapeutic vulnerability and survival dependency in MM cells. PRMT1, a major Type I PRMT enzyme, catalyzes the asymmetric transfer of methyl groups to arginine residues, influencing gene transcription and protein function through post-translational modification. Dysregulation or overexpression of PRMT1 has been observed in various malignancies including MM and is linked to chemoresistance. Treatment with the Type I PRMT inhibitor GSK3368715 resulted in a dose-dependent reduction in cell survival across a panel of MM cell lines. This was accompanied by reduced levels of asymmetric dimethylation of arginine (ADMA) and increased arginine monomethylation (MMA) in MM cells. Cell cycle analysis revealed an accumulation of cells in the G0/G1 phase and a reduction in the S phase upon GSK3368715 treatment. Additionally, PRMT1 inhibition led to a significant downregulation of genes involved in cell proliferation, DNA replication, and DNA damage response (DDR), likely inducing genomic instability and impairing tumor growth. This was supported by Reverse Phase Protein Array (RPPA) analyses, which revealed a significant reduction in levels of proteins associated with cell cycle regulation and DDR pathways. Overall, our findings indicate that MM cells critically depend on PRMT1 for survival, highlighting the therapeutic potential of PRMT1 inhibition in treating MM.

The online version contains supplementary material available at 10.1186/s12885-025-15104-w.