title: Frequent pathway mutations of splicing machinery in myelodysplasia.
abstract: Myelodysplastic syndromes and related disorders (myelodysplasia) are a heterogeneous group of myeloid neoplasms showing deregulated blood cell production with evidence of myeloid dysplasia and a predisposition to acute myeloid leukaemia, whose pathogenesis is only incompletely understood. Here we report whole-exome sequencing of 29 myelodysplasia specimens, which unexpectedly revealed novel pathway mutations involving multiple components of the RNA splicing machinery, including U2AF35, ZRSR2, SRSF2 and SF3B1. In a large series analysis, these splicing pathway mutations were frequent (∼45 to ∼85%) in, and highly specific to, myeloid neoplasms showing features of myelodysplasia. Conspicuously, most of the mutations, which occurred in a mutually exclusive manner, affected genes involved in the 3'-splice site recognition during pre-mRNA processing, inducing abnormal RNA splicing and compromised haematopoiesis. Our results provide the first evidence indicating that genetic alterations of the major splicing components could be involved in human pathogenesis, also implicating a novel therapeutic possibility for myelodysplasia.
authors: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Kenichi
authors: K
authors: Yoshida
authors: Masashi
authors: M
authors: Sanada
authors: Yuichi
authors: Y
authors: Shiraishi
authors: Daniel
authors: D
authors: Nowak
authors: Yasunobu
authors: Y
authors: Nagata
authors: Ryo
authors: R
authors: Yamamoto
authors: Yusuke
authors: Y
authors: Sato
authors: Aiko
authors: A
authors: Sato-Otsubo
authors: Ayana
authors: A
authors: Kon
authors: Masao
authors: M
authors: Nagasaki
authors: George
authors: G
authors: Chalkidis
authors: Yutaka
authors: Y
authors: Suzuki
authors: Masashi
authors: M
authors: Shiosaka
authors: Ryoichiro
authors: R
authors: Kawahata
authors: Tomoyuki
authors: T
authors: Yamaguchi
authors: Makoto
authors: M
authors: Otsu
authors: Naoshi
authors: N
authors: Obara
authors: Mamiko
authors: M
authors: Sakata-Yanagimoto
authors: Ken
authors: K
authors: Ishiyama
authors: Hiraku
authors: H
authors: Mori
authors: Florian
authors: F
authors: Nolte
authors: Wolf-Karsten
authors: WK
authors: Hofmann
authors: Shuichi
authors: S
authors: Miyawaki
authors: Sumio
authors: S
authors: Sugano
authors: Claudia
authors: C
authors: Haferlach
authors: H Phillip
authors: HP
authors: Koeffler
authors: Lee-Yung
authors: LY
authors: Shih
authors: Torsten
authors: T
authors: Haferlach
authors: Shigeru
authors: S
authors: Chiba
authors: Hiromitsu
authors: H
authors: Nakauchi
authors: Satoru
authors: S
authors: Miyano
authors: Seishi
authors: S
authors: Ogawa
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D059472:Exome / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics*; D012261:Ribonucleoproteins / Q000235:genetics; D017381:Spliceosomes / Q000235:genetics; D000072668:Splicing Factor U2AF
chemical_list: D009687:Nuclear Proteins; D022821:RNA Splice Sites; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human