Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes

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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 protein1,2. 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.

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Figure 1: U2AF1 mutations found in individuals with MDS.
Figure 2: Impact of U2AF1 mutations on clinical outcome.
Figure 3: U2AF1 p.Ser34Phe alteration induces splicing alterations in 293T cells.

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This work was supported by US National Institutes of Health grants R01HL082973 (T.A.G.), RC2HL102927 (T.A.G.), U54HG003079 (R.K.W.) and P01CA101937 (T.J.L.) and a Howard Hughes Medical Institute Physician-Scientist Early Career Award (M.J.W.). Technical assistance was provided by the Alvin J. Siteman Cancer Center High Speed Cell Sorting Core, the Molecular and Genomic Analysis Core, the Biomedical Informatics Core and the Tissue Procurement Core, which are all supported by the National Cancer Institute Cancer Center Support Grant P30CA91842. Additional technical assistance was provided by M. Izumi. We thank K. Ohno (Nagoya University Graduate School of Medicine, Japan) for minigene constructs. We thank K. Hall (Washington University School of Medicine) for helpful scientific discussions.

Author information

The project leaders were T.A.G., D.S., L.D. and M.J.W. Study design and project conception were performed by T.A.G., L.D., D.C.L., M.H.T., P.W., J.F.D., E.R.M., T.J.L., R.K.W. and M.J.W. Sequence and data analysis were performed by D.S., L.D., C.C.H., D.C.K., D.E.L., M.D.M., D.J.D., R.M.A., R.S.F., H.S., J.K.-V. and M.O. In vitro splicing assays, PCR or gene expression analyses were performed by T.O.-O., C.L.L., J.S., K.K. and T.N. Clinical data management, specimen acquisition or statistical analyses were performed by M.G., S.H. and J.B. Hematopathology was performed by J.L.F. Manuscript preparation was performed by T.A.G., D.S., L.D., D.C.L., J.F.D., E.R.M., T.J.L., R.K.W. and M.J.W.

Correspondence to Matthew J Walter.

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