Monday, December 19, 2011 (Last Updated: 12/20/2011)MONDAY, Dec. 19 (HealthDay News) -- Patients with myelodysplastic syndromes (MDS), with a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1, may be more likely to progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML), according to a letter published online Dec. 11 in Nature Genetics.
Timothy A. Graubert, M.D., from Washington University in St. Louis, and colleagues used whole-genome sequencing to investigate the somatic mutations in a sample from an individual with sAML. The loci containing the mutations were genotyped in a matched sample from 150 individuals with de novo MDS.
The investigators found that 13 participants with de novo MDS (8.7 percent) had a recurrent missense mutation affecting Ser34 in U2AF1. There was evidence to suggest that this mutation was associated with an increased risk of progression to sAML. Mutations in U2AF1 are located in the highly conserved zinc fingers of the protein. In vitro reporter assays revealed enhanced splicing and exon skipping with mutant U2AF1.
"The identification of somatic mutations in spliceosome genes in MDS by our group and others raises the possibility that mutations in splicing factors, including U2AF1, may be responsible for the observed alterations of splicing in cancer," the authors write. "Identification of key target genes affected by U2AF1 mutations will be crucial to our understanding of how these mutations contribute to MDS pathogenesis."
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