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PRMT5 supports multiple oncogenic pathways in mantle cell lymphoma
Shelby L Sloan1,2, Fiona Brown1, Mackenzie Long1,2
1Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH.
Blood
|June 2, 2023
Summary
Targeting Protein Arginine Methyltransferase 5 (PRMT5) with PRT-382 shows promise for mantle cell lymphoma (MCL). This approach halts cancer growth and induces cell death, offering new hope for relapsed/refractory MCL patients.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Mantle cell lymphoma (MCL) is an aggressive B-cell cancer with poor prognosis, especially after treatment failure.
- Protein arginine methyltransferase 5 (PRMT5) is overexpressed in MCL and drives cancer progression through epigenetic and posttranslational modifications.
- Current treatment options for relapsed/refractory MCL are limited, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the antitumor activity of PRMT5 inhibition in mantle cell lymphoma (MCL).
- To elucidate the molecular mechanisms underlying PRMT5's role in MCL pathogenesis and response to targeted therapy.
- To identify potential biomarkers for predicting treatment response in MCL.
Main Methods:
- Utilized integrated transcriptomics in vitro and in vivo MCL models.
- Administered a selective small-molecule inhibitor of PRMT5, PRT-382.
- Analyzed transcriptional reprogramming, cell cycle regulation, apoptosis, and signaling pathway modulation.
Main Results:
- PRMT5 inhibition with PRT-382 induced cell growth arrest and apoptosis in MCL models.
- Therapeutic benefit was observed in patient-derived MCL xenografts.
- PRMT5 inhibition restored cell cycle control, induced apoptosis, and modulated B-cell receptor signaling pathways.
Conclusions:
- Pharmacologic inhibition of PRMT5 is a promising therapeutic strategy for relapsed/refractory MCL.
- Biomarkers such as MTAP/CDKN2A deletion and wild-type TP53 may predict favorable responses to PRMT5 inhibition.
- Targeting PRMT5 warrants further clinical investigation for MCL treatment.
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