Functional significance of U2AF1 S34F mutations in lung adenocarcinomas

Mohammad S. Esfahani, Luke J. Lee, Young-Jun Jeon, Ryan A. Flynn, Henning Stehr, Angela B. Hui, Noriko Ishisoko, Eric Kildebeck, Aaron M. Newman, Scott V. Bratman, Matthew H. Porteus, Howard Y. Chang, Ash A. Alizadeh () and Maximilian Diehn ()
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Mohammad S. Esfahani: Stanford University
Luke J. Lee: Stanford University
Young-Jun Jeon: Stanford University
Ryan A. Flynn: Stanford University
Henning Stehr: Stanford University
Angela B. Hui: Stanford University
Noriko Ishisoko: Stanford University
Eric Kildebeck: Stanford University
Aaron M. Newman: Stanford University
Scott V. Bratman: Stanford University
Matthew H. Porteus: Stanford University
Howard Y. Chang: Stanford University
Ash A. Alizadeh: Stanford University
Maximilian Diehn: Stanford University

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract The functional role of U2AF1 mutations in lung adenocarcinomas (LUADs) remains incompletely understood. Here, we report a significant co-occurrence of U2AF1 S34F mutations with ROS1 translocations in LUADs. To characterize this interaction, we profiled effects of S34F on the transcriptome-wide distribution of RNA binding and alternative splicing in cells harboring the ROS1 translocation. Compared to its wild-type counterpart, U2AF1 S34F preferentially binds and modulates splicing of introns containing CAG trinucleotides at their 3′ splice junctions. The presence of S34F caused a shift in cross-linking at 3′ splice sites, which was significantly associated with alternative splicing of skipped exons. U2AF1 S34F induced expression of genes involved in the epithelial-mesenchymal transition (EMT) and increased tumor cell invasion. Finally, S34F increased splicing of the long over the short SLC34A2-ROS1 isoform, which was also associated with enhanced invasiveness. Taken together, our results suggest a mechanistic interaction between mutant U2AF1 and ROS1 in LUAD.

Date: 2019
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DOI: 10.1038/s41467-019-13392-y

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