Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes

Timothy A. Graubert, Dong Shen, Li Ding, Theresa Okeyo-Owuor, Cara L. Lunn, Jin Shao, Kilannin Krysiak, Christopher C. Harris, Daniel C. Koboldt, David E. Larson, Michael D. McLellan, David J. Dooling, Rachel M. Abbott, Robert S. Fulton, Heather Schmidt, Joelle Kalicki-Veizer, Michelle O'Laughlin, Marcus Grillot, Jack Baty, Sharon HeathJohn L. Frater, Talat Nasim, Daniel C. Link, Michael H. Tomasson, Peter Westervelt, John F. DiPersio, Elaine R. Mardis, Timothy J. Ley, Richard K. Wilson, Matthew J. Walter

    Research output: Contribution to journalArticlepeer-review

    476 Citations (Scopus)


    Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform an unbiased comprehensive screen to discover the somatic mutations in a sample from an individual with sAML and genotyped the loci containing these mutations in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in 13 out of 150 (8.7%) subjects with de novo MDS, and we found suggestive evidence of an increased risk of progression to sAML associated with this mutation. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3' end of introns, and the alterations in U2AF1 are located in highly conserved zinc fingers of this protein(1,2). Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This previously unidentified, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis.
    Original languageEnglish
    Pages (from-to)53 - U77
    Number of pages5
    JournalNature Genetics
    Issue number1
    Publication statusPublished - Jan 2012


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