Frequent pathway mutations of splicing machinery in myelodysplasia

被引：1358

作者：

Yoshida, Kenichi ^{[1
]}

Sanada, Masashi ^{[1
]}

Shiraishi, Yuichi ^{[2
]}

Nowak, Daniel ^{[3
]}

Nagata, Yasunobu ^{[1
]}

Yamamoto, Ryo ^{[4
]}

Sato, Yusuke ^{[1
]}

Sato-Otsubo, Aiko ^{[1
]}

Kon, Ayana ^{[1
]}

Nagasaki, Masao ^{[5
]}

Chalkidis, George ^{[6
]}

Suzuki, Yutaka ^{[7
]}

Shiosaka, Masashi ^{[1
]}

Kawahata, Ryoichiro ^{[1
]}

Yamaguchi, Tomoyuki ^{[8
]}

Otsu, Makoto ^{[4
]}

Obara, Naoshi ^{[9
]}

Sakata-Yanagimoto, Mamiko ^{[9
]}

Ishiyama, Ken ^{[10
]}

Mori, Hiraku ^{[11
]}

Nolte, Florian ^{[3
]}

Hofmann, Wolf-Karsten ^{[3
]}

Miyawaki, Shuichi ^{[10
]}

Sugano, Sumio ^{[7
]}

Haferlach, Claudia ^{[12
]}

Koeffler, H. Phillip ^{[13
,14
]}

Shih, Lee-Yung ^{[15
]}

Haferlach, Torsten ^{[12
]}

Chiba, Shigeru ^{[9
]}

Nakauchi, Hiromitsu ^{[4
,8
]}

Miyano, Satoru ^{[2
,6
]}

Ogawa, Seishi ^{[1
]}

机构：

[1] Univ Tokyo, Grad Sch Med, Canc Genom Project, Bunkyo Ku, Tokyo 1138655, Japan

[2] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab DNA Informat Anal,Minato Ku, Tokyo 1088639, Japan

[3] Univ Heidelberg, Dept Hematol & Oncol, Med Fac Manheim, D-68167 Mannheim, Germany

[4] Univ Tokyo, Div Stem Cell Therapy, Ctr Stem Cell Biol & Regenerat Med, Inst Med Sci,Minato Ku, Tokyo 1088639, Japan

[5] Univ Tokyo, Lab Funct Genom, Ctr Human Genome, Inst Med Sci,Minato Ku, Tokyo 1088639, Japan

[6] Univ Tokyo, Lab Sequence Data Anal, Ctr Human Genome, Inst Med Sci,Minato Ku, Tokyo 1088639, Japan

[7] Univ Tokyo, Div Syst Biomed Technol, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan

[8] Japan Sci & Technol Agcy, Nakauchi Stem Cell & Organ Regenerat Project, Minato Ku, Tokyo 1088639, Japan

[9] Univ Tsukuba, Dept Hematol, Inst Clin Med, Tsukuba, Ibaraki 3058571, Japan

[10] Tokyo Metropolitan Otsuka Hosp, Div Hematol, Toshima Ku, Tokyo 1700005, Japan

[11] Showa Univ, Fujigaoka Hosp, Div Hematol, Aoba Ku, Kanagawa 2278501, Japan

[12] Munich Leukemia Lab, D-81377 Munich, Germany

[13] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA

[14] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117456, Singapore

[15] Chang Gung Univ, Chang Gung Mem Hosp, Dept Internal Med, Div Hematol Oncol, Taipei 105, Taiwan

来源：

NATURE | 2011年 / 478卷 / 7367期

基金：

日本学术振兴会;

关键词：

ACUTE MYELOID-LEUKEMIA; PRE-MESSENGER-RNA; DEVELOPMENTAL DISORDER; SOMATIC MUTATIONS; U4ATAC SNRNA; GENOME; GENE; IDENTIFICATION; SPLICEOSOME; COMPONENT;

D O I：

10.1038/nature10496

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 (similar to 45 to similar 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 inhuman pathogenesis, also implicating a novel therapeutic possibility for myelodysplasia.

引用

页码：64 / 69

页数：6

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