# Understanding resistance mechanisms to protein arginine methyltransransferase Inhibitors in Lymphoma

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $659,913

## Abstract

PROJECT SUMMARY/ABSTRACT
Non-Hodgkin’s lymphoma (NHL) is among the most common cancers and despite current therapies many
patients relapse from their disease. Recent discoveries have implicated epigenetic mechanisms and non-
classical oncogenic programs as dysregulated in patients with B-cell lymphoma. Protein arginine
methyltransferase-5 (PRMT5), the major enzyme responsible for the arginine symmetric dimethylation of
histones and non-histone proteins, plays an important role in lymphomagenesis, controlling the growth of
transformed B cells. PRMT5 is overexpressed in lymphoma and may represent a novel therapeutic target for
this disease. In order to assess what regulators drive resistance, we performed a genome wide CRISPR screen.
Surprisingly, we uncovered the RNA binding protein MUSASHI2 (MSI2) as the top hit. MSI2 is an RNA binding
protein that has been implicated as a stem related protein that is the most highly expressed in the most
aggressive cancers but its role in B-cell lymphoma is not known. Our preliminary data suggests that MSI2 is
highly expressed in lymphomas and reduction reduces proliferation which is further reduced by PRMT5 inhibition.
We also discovered new post-translational modifications mediated by PRMT1 and PRMT5 in B-cell lymphoma
and demonstrated a functional requirement for these newly discovered modifications. We propose to study this
new PRMT-MSI2 axis in driving lymphomagenesis using genetic mouse models, human lymphoma cell lines
and patient samples. Furthermore, we utilize technological innovations to study direct MSI2 targets and the
mechanism for how MSI2 mediates resistance to PRMT5 inhibition in lymphoma. These studies have broad
implication to how RBPs can become dysregulated and their function controlled by PRMTs in B-cell lymphoma.

## Key facts

- **NIH application ID:** 10808196
- **Project number:** 5R01CA274249-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Michael Kharas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $659,913
- **Award type:** 5
- **Project period:** 2023-03-13 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808196

## Citation

> US National Institutes of Health, RePORTER application 10808196, Understanding resistance mechanisms to protein arginine methyltransransferase Inhibitors in Lymphoma (5R01CA274249-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10808196. Licensed CC0.

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