title: Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes.
abstract: 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. 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.
authors.affiliation: Department of Internal Medicine, Division of Oncology, Washington University, St. Louis, Missouri, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Graubert
authors.forename: Dong
authors.initials: D
authors.lastname: Shen
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Theresa
authors.initials: T
authors.lastname: Okeyo-Owuor
authors.forename: Cara L
authors.initials: CL
authors.lastname: Lunn
authors.forename: Jin
authors.initials: J
authors.lastname: Shao
authors.forename: Kilannin
authors.initials: K
authors.lastname: Krysiak
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Harris
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Koboldt
authors.forename: David E
authors.initials: DE
authors.lastname: Larson
authors.forename: Michael D
authors.initials: MD
authors.lastname: McLellan
authors.forename: David J
authors.initials: DJ
authors.lastname: Dooling
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Abbott
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.forename: Heather
authors.initials: H
authors.lastname: Schmidt
authors.forename: Joelle
authors.initials: J
authors.lastname: Kalicki-Veizer
authors.forename: Michelle
authors.initials: M
authors.lastname: O'Laughlin
authors.forename: Marcus
authors.initials: M
authors.lastname: Grillot
authors.forename: Jack
authors.initials: J
authors.lastname: Baty
authors.forename: Sharon
authors.initials: S
authors.lastname: Heath
authors.forename: John L
authors.initials: JL
authors.lastname: Frater
authors.forename: Talat
authors.initials: T
authors.lastname: Nasim
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
authors.forename: Michael H
authors.initials: MH
authors.lastname: Tomasson
authors.forename: Peter
authors.initials: P
authors.lastname: Westervelt
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walter
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D012326:RNA Splicing; D012261:Ribonucleoproteins / Q000235:genetics*; D000072668:Splicing Factor U2AF
chemical_list: D009687:Nuclear Proteins; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human