Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes

• Published in: Nature genetics Vol. 44; no. 1; pp. 53 - 57
• Main Authors: Graubert, Timothy A, Shen, Dong, Ding, Li, Okeyo-Owuor, Theresa, Lunn, Cara L, Shao, Jin, Krysiak, Kilannin, Harris, Christopher C, Koboldt, Daniel C, Larson, David E, McLellan, Michael D, Dooling, David J, Abbott, Rachel M, Fulton, Robert S, Schmidt, Heather, Kalicki-Veizer, Joelle, O'Laughlin, Michelle, Grillot, Marcus, Baty, Jack, Heath, Sharon, Frater, John L, Nasim, Talat, Link, Daniel C, Tomasson, Michael H, Westervelt, Peter, DiPersio, John F, Mardis, Elaine R, Ley, Timothy J, Wilson, Richard K, Walter, Matthew J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 11-12-2011; Nature Publishing Group
• Subjects: 631/208/737; 692/699/67/1990/1673; Adult; Aged; Aged, 80 and over; Agriculture; Animal Genetics and Genomics; Base Sequence; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Chemotherapy; Disease Progression; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Function; Genetic testing; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Hematologic and hematopoietic diseases; Human Genetics; Humans; letter; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Molecular Sequence Data; Mutation; Mutation, Missense; Myelodysplastic syndromes; Myelodysplastic Syndromes - genetics; Nuclear Proteins - genetics; Pathogenesis; Ribonucleoproteins - genetics; RNA Splicing; Splicing Factor U2AF; Stem cells; Malignant hemopathy; Mutation; Recurrent; Splicing factor; Myelodysplastic syndrome; Cancer
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.1031

Matthew Walter and colleagues report the whole-genome sequencing of a secondary acute myeloid leukemia sample and a matched normal tissue sample. Further analysis of additional subjects identified recurrent mutations in
U2AF1
in 13/150 (8.7%) individuals with myelodysplastic syndrome.
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.