TY - JOUR
T1 - Frequent pathway mutations of splicing machinery in myelodysplasia
AU - Yoshida, Kenichi
AU - Sanada, Masashi
AU - Shiraishi, Yuichi
AU - Nowak, Daniel
AU - Nagata, Yasunobu
AU - Yamamoto, Ryo
AU - Sato, Yusuke
AU - Sato-Otsubo, Aiko
AU - Kon, Ayana
AU - Nagasaki, Masao
AU - Chalkidis, George
AU - Suzuki, Yutaka
AU - Shiosaka, Masashi
AU - Kawahata, Ryoichiro
AU - Yamaguchi, Tomoyuki
AU - Otsu, Makoto
AU - Obara, Naoshi
AU - Sakata-Yanagimoto, Mamiko
AU - Ishiyama, Ken
AU - Mori, Hiraku
AU - Nolte, Florian
AU - Hofmann, Wolf Karsten
AU - Miyawaki, Shuichi
AU - Sugano, Sumio
AU - Haferlach, Claudia
AU - Koeffler, H. Phillip
AU - Shih, Lee Yung
AU - Haferlach, Torsten
AU - Chiba, Shigeru
AU - Nakauchi, Hiromitsu
AU - Miyano, Satoru
AU - Ogawa, Seishi
N1 - Funding Information:
Acknowledgements This work was supported by Grant-in-Aids from the Ministry of Health, Labor and Welfare of Japan and from the Ministry of Education, Culture, Sports, Science and Technology, and also by the Japan Society for the Promotion of Science (JSPS) through the ‘Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program)’, initiated by the Council for Science and Technology Policy (CSTP). pGCDNsamIRESEGFP vector was a gift from M. Onodera. We thank Y. Mori, O. Hagiwara, M. Nakamura and N. Mizota for their technical assistance. We are also grateful to K. Ikeuchi and M. Ueda for their continuous encouragement throughout the study.
PY - 2011/10/6
Y1 - 2011/10/6
N2 - 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.
AB - 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.
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U2 - 10.1038/nature10496
DO - 10.1038/nature10496
M3 - Article
C2 - 21909114
AN - SCOPUS:80053900941
VL - 478
SP - 64
EP - 69
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7367
ER -