title: Patterns of missplicing due to somatic U2AF1 mutations in myeloid neoplasms.
abstract: Recently, recurrent mutations of spliceosomal genes were frequently identified in myeloid malignancies, as well as other types of cancers. One of these spliceosomal genes, U2AF1, was affected by canonical somatic mutations in aggressive type of myeloid malignancies. We hypothesized that U2AF1 mutations causes defects of splicing (missplicing) in specific genes and that such misspliced genes might be important in leukemogenesis. We analyzed RNA deep sequencing to compare splicing patterns of 201 837 exons between the cases with U2AF1 mutations (n = 6) and wild type (n = 14). We identified different alternative splicing patterns in 35 genes comparing cells with mutant and wild-type U2AF1. U2AF1 mutations are associated with abnormal splicing of genes involved in functionally important pathways, such as cell cycle progression and RNA processing. In addition, many of these genes are somatically mutated or deleted in various cancers. Of note is that the alternative splicing patterns associated with U2AF1 mutations were associated with specific sequence signals at the affected splice sites. These novel observations support the hypothesis that U2AF1 mutations play a significant role in myeloid leukemogenesis due to selective missplicing of tumor-associated genes.
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Przychodzen
authors.forename: Andres
authors.initials: A
authors.lastname: Jerez
authors.forename: Kathryn
authors.initials: K
authors.lastname: Guinta
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
authors.forename: Richard
authors.initials: R
authors.lastname: Padgett
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
mesh_terms: D017398:Alternative Splicing; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D019337:Hematologic Neoplasms / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D009190:Myelodysplastic Syndromes / Q000235:genetics; D009196:Myeloproliferative Disorders / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D012261:Ribonucleoproteins / Q000235:genetics*; D000072668:Splicing Factor U2AF
chemical_list: D009687:Nuclear Proteins; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human