TY - JOUR
T1 - Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes
AU - Graubert, Timothy A.
AU - Shen, Dong
AU - Ding, Li
AU - Okeyo-Owuor, Theresa
AU - Lunn, Cara L.
AU - Shao, Jin
AU - Krysiak, Kilannin
AU - Harris, Christopher C.
AU - Koboldt, Daniel C.
AU - Larson, David E.
AU - McLellan, Michael D.
AU - Dooling, David J.
AU - Abbott, Rachel M.
AU - Fulton, Robert S.
AU - Schmidt, Heather
AU - Kalicki-Veizer, Joelle
AU - O'Laughlin, Michelle
AU - Grillot, Marcus
AU - Baty, Jack
AU - Heath, Sharon
AU - Frater, John L.
AU - Nasim, Talat
AU - Link, Daniel C.
AU - Tomasson, Michael H.
AU - Westervelt, Peter
AU - Dipersio, John F.
AU - Mardis, Elaine R.
AU - Ley, Timothy J.
AU - Wilson, Richard K.
AU - Walter, Matthew J.
N1 - Funding Information:
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.
PY - 2012/1
Y1 - 2012/1
N2 - 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 3ĝ€2 end of introns, and the alterations in U2AF1 are located in highly conserved zinc fingers of this protein. 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.
AB - 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 3ĝ€2 end of introns, and the alterations in U2AF1 are located in highly conserved zinc fingers of this protein. 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.
UR - http://www.scopus.com/inward/record.url?scp=84555192302&partnerID=8YFLogxK
U2 - 10.1038/ng.1031
DO - 10.1038/ng.1031
M3 - Article
C2 - 22158538
AN - SCOPUS:84555192302
SN - 1061-4036
VL - 44
SP - 53
EP - 57
JO - Nature Genetics
JF - Nature Genetics
IS - 1
ER -