MYC-mediated maintenance of proper mRNA splicing is essential for lymphomagenesis.

  • Major finding: MYC-mediated maintenance of proper mRNA splicing is essential for lymphomagenesis.

  • Mechanism: MYC directly upregulates the expression of core small ribonucleoprotein particle assembly genes.

  • Impact: Spliceosome-targeted therapy may prove effective in MYC-driven hematologic malignancies.

The MYC oncogene drives tumor proliferation in multiple cancer types by influencing gene transcription, protein translation, and DNA replication. However, current therapeutic strategies to target MYC have thus far been unsuccessful. Koh, Bezzi, and colleagues found that MYC directly induces the transcription of genes encoding core spliceosome machinery components in both human and murine lymphoma models. Among the upregulated targets were small nuclear ribonucleoprotein particle (snRNP) assembly genes, including the gene encoding the critical enzymatic subunit protein arginine methyltransferase 5 (PRMT5). Expression of these genes correlated with high MYC levels in human lymphoma and leukemia, and PRMT5 levels accurately predicted poor prognosis and decreased survival in patients with large diffuse B-cell lymphomas. In addition, lymphoma development in Eμ-myc;Prmt5+/− mice was delayed, implicating PRMT5 in MYC-driven tumorigenesis. Consistent with this finding, acute deletion of Prmt5 reduced the viability of Eμ-myc B cells and increased G1 arrest and apoptosis ex vivo, and PRMT5 was required for the maintenance of MYC-driven lymphomas in vivo. Deletion of Prmt5 in both murine and human lymphoma cell lines resulted in decreased methylation of Sm proteins and increased aberrant splicing of pre-mRNAs with weak 5′ donor sites via exon skipping and intron retention. Similarly, depletion of MYC in lymphoma cell lines decreased PRMT5 levels and resulted in aberrant splicing events, supporting the idea that MYC-dependent regulation of PRMT5 is essential for proper mRNA splicing in lymphoma. Forced expression of alternatively spliced transcripts regulated by MYC/PRMT5, including Atr, Ep400, and Dvl1, using antisense oligonucleotides decreased Eμ-myc B-cell viability and increased apoptosis, mimicking the effects of PRMT5 depletion. Overall, these results provide evidence that MYC regulates the core splicing machinery to maintain the fidelity of mRNA splicing during lymphomagenesis and suggest that targeted inhibition of spliceosome components may be effective in MYC-driven tumors.

Koh CM, Bezzi M, Low DH, Ang WX, Teo SX, Gay FP, et al. MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis. Nature 2015 May 11 [Epub ahead of print].

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