No abstract

Deregulated expression of the MYC transcription factor occurs in a majority of human cancers and correlates with high proliferation, reprogrammed cellular metabolism and poor prognosis. Over-expressed MYC binds to virtually all active promoters within a cell, although with different binding affinities, and modulates the expression of distinct subsets of genes. However, the critical effectors of MYC in tumorigenesis remain largely unknown. Here, we show that during lymphomagenesis in Eµ-myc transgenic mice, MYC directly up-regulates the transcription of the core snRNP assembly genes, including Prmt5, an arginine methyltransferase that methylates Sm proteins. This coordinated regulatory effect is critical for snRNP biogenesis, effective mRNA splicing, cell survival and proliferation. Indeed, Prmt5 haplo-insufficiency significantly delays lymphoma onset in Eµ-myc transgenic mice and the acute deletion of PRMT5 in established lymphomas enhances the survival of tumor-bearing animals. In human lymphomas and leukemias, the expression of core snRNP genes also correlates with that of MYC, and PRMT5 knockdown results in aberrant pre-mRNA splicing and loss of viability. In both human or mouse lymphomas cells, MYC knockdown also reduces the expression of core snRNP components, causing aberrant pre-mRNA splicing. Finally, we identify pre-mRNAs that are particularly sensitive to perturbation of the MYC-PRMT5 axis, resulting in either intron retention or exon skipping. Using antisense oligonucleotides (ASOs), we mimic these splicing defects and demonstrate their individual contribution to the anti-proliferative/apoptotic phenotype observed in Eµ-myc B-cells. Thus, coordinate regulation of the core snRNP assembly machinery and PRMT5 is critical for the maintenance of normal pre-mRNA splicing and cell survival upon oncogenic activation of c-myc, pointing to PRMT5 methyl-transferase activity as a potential therapeutic target in MYC-driven tumors. Citation Format: Cheryl Koh, Marco Bezzi, Diana Low, WeiXia Ang, ShunXie Teo, Florence Gay, Muthafar Al Haddawi, SooYong Tan, Motomi Osato, Arianna Sabo', KengBoon Wee, Bruno Amati, Ernesto Guccione. Regulation of the core pre-mRNA splicing machinery by MYC and PRMT5 is essential to sustain lymphomagenesis. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B30.