Frequent pathway mutations of splicing machinery in myelodysplasia

Kenichi Yoshida, Masashi Sanada, Yuichi Shiraishi, Daniel Nowak, Yasunobu Nagata, Ryo Yamamoto, Yusuke Sato, Aiko Sato-Otsubo, Ayana Kon, Masao Nagasaki, George Chalkidis, Yutaka Suzuki, Masashi Shiosaka, Ryoichiro Kawahata, Tomoyuki Yamaguchi, Makoto Otsu, Naoshi Obara, Mamiko Sakata-Yanagimoto, Ken Ishiyama, Hiraku MoriFlorian Nolte, Wolf Karsten Hofmann, Shuichi Miyawaki, Sumio Sugano, Claudia Haferlach, H. Phillip Koeffler, Lee Yung Shih, Torsten Haferlach, Shigeru Chiba, Hiromitsu Nakauchi, Satoru Miyano, Seishi Ogawa*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

1617 Scopus citations


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 (∼445 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.

Original languageEnglish
Pages (from-to)64-69
Number of pages6
Issue number7367
StatePublished - 06 10 2011


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