Related Experiment Video

Updated: Aug 27, 2025

Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

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TP53 mutations and RNA-binding protein MUSASHI-2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma

Tatiana Erazo1, Chiara M Evans1,2, Daniel Zakheim3

  • 1Molecular Pharmacology Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Nature Communications
|September 27, 2022
PubMed

Insights

TP53 mutations and MUSASHI2 (MSI2) influence sensitivity to Protein Arginine Methyltransferase 5 (PRMT5) inhibitors. Combining PRMT5 inhibition with MSI2 or BCL-2 targeting offers a novel therapeutic strategy for lymphoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Protein Arginine Methyltransferase 5 (PRMT5) is a therapeutic target in various cancers.
  • Understanding resistance mechanisms to PRMT5 inhibitors is crucial for effective treatment strategies.

Purpose of the Study:

  • To identify genetic drivers of sensitivity and resistance to PRMT5 inhibition.
  • To explore combination therapies involving PRMT5 inhibition for lymphoma treatment.

Main Methods:

  • Genome-wide CRISPR/Cas9 screening was employed to identify key genes.
  • Pharmacological inhibition of PRMT5, MSI2, and BCL-2 was assessed.
  • Synergistic effects on cell growth, gene expression, and protein translation were analyzed.

Main Results:

  • TP53 alterations (deletion, R248W mutation) confer resistance to PRMT5 inhibitor GSK-591.
  • MUSASHI2 (MSI2) acts as a resistance driver and its inhibition synergizes with PRMT5 inhibitors.
  • Combined inhibition of PRMT5 and MSI2, or PRMT5 and BCL-2, shows synergistic effects in lymphoma cells.

Conclusions:

  • TP53 and MSI2 are critical regulators of PRMT5 inhibitor response.
  • Dual targeting of PRMT5 with MSI2 or BCL-2 represents a promising therapeutic approach for lymphoma.
  • This strategy warrants further investigation for clinical application in lymphoma patients.

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