# Targeting PRMT5 in Adult T-Cell Leukemia/Lymphoma: Opportunities and Challenges

## TL;DR

This review explores the potential of targeting PRMT5, a protein linked to cancer progression, as a new treatment strategy for the aggressive T-cell cancer ATLL.

## Contribution

The paper provides a comprehensive review of PRMT5's role in ATLL and evaluates its potential as a therapeutic target.

## Key findings

- PRMT5 is overexpressed in HTLV-1-infected T cells and contributes to their transformation.
- Pharmacologic inhibition of PRMT5 selectively impairs the survival of infected T cells in preclinical models.
- Combination therapies and tumor-selective inhibitors are proposed as future strategies for ATLL treatment.

## Abstract

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy caused by persistent infection with human T-cell leukemia virus type 1 (HTLV-1). ATLL remains difficult to treat despite intensive chemotherapy, antiviral therapy, and hematopoietic stem cell transplantation. The limited durability of current treatment strategies highlights the need for mechanism-based therapeutic approaches. Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that regulates transcription, RNA splicing, DNA damage responses, and immune signaling through symmetric dimethylation of histone and non-histone substrates. PRMT5 is frequently overexpressed across hematologic and solid tumors. Preclinical studies indicate that PRMT5 expression is elevated during HTLV-1-mediated T-cell transformation and that pharmacologic inhibition of PRMT5 selectively impairs the survival and transformation of infected T cells in vitro and in vivo. In this review, we highlight the current understanding of PRMT5 biology in cancer, summarize preclinical studies supporting PRMT5 as a therapeutic target in ATLL, and discuss key challenges to future clinical translation. We also discuss emerging approaches such as rational combination therapies and tumor-selective PRMT5 inhibitors as potential paths toward treatment for ATLL.