Publication Date:
2011-09-13
Description:
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 ( approximately 45 to approximately 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yoshida, Kenichi -- Sanada, Masashi -- Shiraishi, Yuichi -- Nowak, Daniel -- Nagata, Yasunobu -- Yamamoto, Ryo -- Sato, Yusuke -- Sato-Otsubo, Aiko -- Kon, Ayana -- Nagasaki, Masao -- Chalkidis, George -- Suzuki, Yutaka -- Shiosaka, Masashi -- Kawahata, Ryoichiro -- Yamaguchi, Tomoyuki -- Otsu, Makoto -- Obara, Naoshi -- Sakata-Yanagimoto, Mamiko -- Ishiyama, Ken -- Mori, Hiraku -- Nolte, Florian -- Hofmann, Wolf-Karsten -- Miyawaki, Shuichi -- Sugano, Sumio -- Haferlach, Claudia -- Koeffler, H Phillip -- Shih, Lee-Yung -- Haferlach, Torsten -- Chiba, Shigeru -- Nakauchi, Hiromitsu -- Miyano, Satoru -- Ogawa, Seishi -- R01 CA026038/CA/NCI NIH HHS/ -- England -- Nature. 2011 Sep 11;478(7367):64-9. doi: 10.1038/nature10496.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21909114" target="_blank"〉PubMed〈/a〉
Keywords:
Alternative Splicing/genetics
;
Exome/genetics
;
Hematopoiesis/genetics
;
Humans
;
Mutation/*genetics
;
Myelodysplastic Syndromes/*genetics
;
Nuclear Proteins/genetics
;
Polymorphism, Single Nucleotide/genetics
;
RNA Splice Sites/genetics
;
RNA Splicing/*genetics
;
Ribonucleoproteins/genetics
;
Spliceosomes/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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