Recurrent Mutations in the U2AF1 Splicing Factor in Myelodysplastic Syndromes

Overview

Journal Nat Genet

Specialty Genetics

Date 2011 Dec 14

PMID 22158538

Citations 340

Authors

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 OLaughlin

Marcus Grillot

Jack Baty

Sharon Heath

John 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

Affiliations

Soon will be listed here.

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.

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