Coordinated Splicing of Regulatory Detained Introns within Oncogenic Transcripts Creates an Exploitable Vulnerability in Malignant Glioma

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Cancer Cell
September 28, 2017

Christian J. Braun, Monica Stanciu, Paul L. Boutz, Jesse C. Patterson, David Calligaris, Fumi Higuchi, Rachit Neupane, Silvia Fenoglio, Daniel P. Cahill, Hiroaki Wakimoto, Nathalie Y.R. Agar, Michael B. Yaffe, Phillip A. Sharp, Michael T. Hemann, Jacqueline A. Lees

Glioblastoma (GBM) is a devastating malignancy with few therapeutic options. We identify PRMT5 in an in vivo GBM shRNA screen and show that PRMT5 knockdown or inhibition potently suppresses in vivo GBM tumors, including patient-derived xenografts. Pathway analysis implicates splicing in cellular PRMT5 dependency, and we identify a biomarker that predicts sensitivity to PRMT5 inhibition. We find that PRMT5 deficiency primarily disrupts the removal of detained introns (DIs). This impaired DI splicing affects proliferation genes, whose downregulation coincides with cell cycle defects, senescence and/or apoptosis.

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