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Functional significance of U2AF1 S34F mutations in lung adenocarcinomas

Author

Listed:
  • Mohammad S. Esfahani

    (Stanford University
    Stanford University
    Stanford University)

  • Luke J. Lee

    (Stanford University)

  • Young-Jun Jeon

    (Stanford University
    Stanford University)

  • Ryan A. Flynn

    (Stanford University)

  • Henning Stehr

    (Stanford University
    Stanford University)

  • Angela B. Hui

    (Stanford University
    Stanford University)

  • Noriko Ishisoko

    (Stanford University)

  • Eric Kildebeck

    (Stanford University)

  • Aaron M. Newman

    (Stanford University
    Stanford University)

  • Scott V. Bratman

    (Stanford University
    Stanford University
    University of Toronto)

  • Matthew H. Porteus

    (Stanford University)

  • Howard Y. Chang

    (Stanford University
    Stanford University)

  • Ash A. Alizadeh

    (Stanford University
    Stanford University
    Stanford University)

  • Maximilian Diehn

    (Stanford University
    Stanford University
    Stanford University)

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.

Suggested Citation

  • 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 & Howar, 2019. "Functional significance of U2AF1 S34F mutations in lung adenocarcinomas," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13392-y
    DOI: 10.1038/s41467-019-13392-y
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