Exploring the Effect of PRMT5 Inhibition on the Intrinsic Apoptotic Pathway in Mantle Cell Lymphoma
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Date
2021-05
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The Ohio State University
Abstract
Mantle Cell Lymphoma (MCL) is an aggressive B-cell malignancy that constitutes 3-6% of all Non-Hodgkin's Lymphomas diagnosed each year. MCL is associated with poor prognosis due to resistance to chemotherapies, high incidence of relapse, and late median age of diagnosis. The average survival of patients with MCL is 5 years, and for those who relapse on targeted therapy, 3-8 months. MCL is currently incurable.
A key driver of MCL pathogenesis is an enzyme called Protein Arginine Methyltransferase-5 (PRMT5), which can post-translationally modify proteins by methylating arginine residues. This allows PRMT5 to alter histones and silence genes that regulate cell growth and proliferation, supporting tumorigenesis. Inhibiting PRMT5 significantly delays disease progression and reduces tumor burden in pre-clinical MCL models.
In our work to explore the effects of PRMT5 inhibition and its potential to reprogram MCL cells, we found that inhibiting PRMT5 results in altered expression of BCL-2 family proteins. BCL-2 family proteins regulate apoptosis at the outer mitochondrial membrane through complex and dynamic binding interactions, and the relative abundance of pro- and anti-apoptotic BCL-2 family proteins determines if a cell will live or die. We hypothesized that PRMT5 inhibition reprograms MCL cells to exhibit a pro-apoptotic physiology by directly and indirectly altering the abundance of BCL-2 family proteins.
BH3 profiling was performed in six MCL cell lines to determine the relevance of each BCL-2 family protein to survival in MCL cells. This assay measures the extent to which a cell commits to apoptosis by relating BH3 inhibitor concentrations to mitochondrial outermembrane permeabilization. BH3 profiling was also performed in control and PRMT5 inhibited cells to determine if the apoptotic threshold was altered with treatment.
Our results show that at baseline, each MCL cell line exhibited a unique BH3 profile, meaning they responded differently overall when challenged with various BH3 mimetic peptides. Western blotting revealed no marked changes in abundance of pro- or anti-apoptotic proteins with PRMT5 inhibition. We observed that four out of the six cell lines responded to PRMT5 inhibition by exhibiting a lowered apoptotic threshold for at least one of the BH3 peptides. This finding emphasizes the heterogeneity of MCL cell lines and demonstrates how the intrinsic apoptotic pathway can be differentially regulated in similar in vitro models.
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Keywords
Cancer Biology, Lymphoma, Apoptosis, Mitochondrial Dynamics