PRMT5 supports multiple oncogenic pathways in mantle cell lymphoma.

TitlePRMT5 supports multiple oncogenic pathways in mantle cell lymphoma.
Publication TypeJournal Article
Year of Publication2023
AuthorsSloan SL, Brown F, Long M, Weigel C, Koirala S, Chung J-H, Pray B, Villagomez L, Hinterschied C, Sircar A, Helmig-Mason JB, Prouty A, Brooks E, Youssef Y, Hanel W, Parekh S, Chan WKeung, Chen Z, Lapalombella R, Sehgal L, Vaddi K, Scherle P, Chen-Kiang S, Di Liberto M, Elemento O, Meydan C, Foox J, Butler D, Mason CE, Baiocchi RA, Alinari L
Date Published2023 Sep 07
KeywordsAdult, Cell Line, Tumor, Humans, Lymphoma, Mantle-Cell, Phosphatidylinositol 3-Kinases, Protein-Arginine N-Methyltransferases, Signal Transduction, Tumor Suppressor Protein p53

Mantle cell lymphoma (MCL) is an incurable B-cell malignancy with an overall poor prognosis, particularly for patients that progress on targeted therapies. Novel, more durable treatment options are needed for patients with MCL. Protein arginine methyltransferase 5 (PRMT5) is overexpressed in MCL and plays an important oncogenic role in this disease via epigenetic and posttranslational modification of cell cycle regulators, DNA repair genes, components of prosurvival pathways, and RNA splicing regulators. The mechanism of targeting PRMT5 in MCL remains incompletely characterized. Here, we report on the antitumor activity of PRMT5 inhibition in MCL using integrated transcriptomics of in vitro and in vivo models of MCL. Treatment with a selective small-molecule inhibitor of PRMT5, PRT-382, led to growth arrest and cell death and provided a therapeutic benefit in xenografts derived from patients with MCL. Transcriptional reprograming upon PRMT5 inhibition led to restored regulatory activity of the cell cycle (p-RB/E2F), apoptotic cell death (p53-dependent/p53-independent), and activation of negative regulators of B-cell receptor-PI3K/AKT signaling (PHLDA3, PTPROt, and PIK3IP1). We propose pharmacologic inhibition of PRMT5 for patients with relapsed/refractory MCL and identify MTAP/CDKN2A deletion and wild-type TP53 as biomarkers that predict a favorable response. Selective targeting of PRMT5 has significant activity in preclinical models of MCL and warrants further investigation in clinical trials.

Alternate JournalBlood
PubMed ID37267517
PubMed Central IDPMC10517215
Grant ListR01 CA252222 / CA / NCI NIH HHS / United States
P30 CA016058 / CA / NCI NIH HHS / United States
P01 CA214274 / CA / NCI NIH HHS / United States
P30 CA196521 / CA / NCI NIH HHS / United States
Related Faculty: 
Selina Chen-Kiang, Ph.D.

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