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 Mori, Florian Nolte, Wolf-Karsten Hofmann, Shuichi Miyawaki, Sumio Sugano, Claudia Haferlach, H. Phillip Koeffler, Lee-Yung Shih, Torsten Haferlach, Shigeru Chiba, Hiromitsu Nakauchi, Satoru Miyano and Seishi Ogawa ()
Additional contact information
Kenichi Yoshida: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Masashi Sanada: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Yuichi Shiraishi: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
Daniel Nowak: Medical Faculty Manheim of the University of Heidelberg, 1–3 Theodor-Kutzer-Ufer, Mannheim 68167, Germany
Yasunobu Nagata: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Ryo Yamamoto: Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
Yusuke Sato: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Aiko Sato-Otsubo: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Ayana Kon: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Masao Nagasaki: Laboratory of Functional Genomics, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
George Chalkidis: Laboratory of Sequence Data Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
Yutaka Suzuki: Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
Masashi Shiosaka: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Ryoichiro Kawahata: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Tomoyuki Yamaguchi: Nakauchi Stem Cell and Organ Regeneration Project, Exploratory Research for Advanced Technology, Japan Science and Technology Agency, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
Makoto Otsu: Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
Naoshi Obara: Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki, 305-8571, Japan
Mamiko Sakata-Yanagimoto: Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki, 305-8571, Japan
Ken Ishiyama: Tokyo Metropolitan Ohtsuka Hospital, 2-8-1 Minami-Ohtsuka, Toshima-ku, Tokyo 170-0005, Japan
Hiraku Mori: Internal Medicine, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama, Kanagawa 227-8501, Japan
Florian Nolte: Medical Faculty Manheim of the University of Heidelberg, 1–3 Theodor-Kutzer-Ufer, Mannheim 68167, Germany
Wolf-Karsten Hofmann: Medical Faculty Manheim of the University of Heidelberg, 1–3 Theodor-Kutzer-Ufer, Mannheim 68167, Germany
Shuichi Miyawaki: Tokyo Metropolitan Ohtsuka Hospital, 2-8-1 Minami-Ohtsuka, Toshima-ku, Tokyo 170-0005, Japan
Sumio Sugano: Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
Claudia Haferlach: Munich Leukemia Laboratory, Max-Lebsche-Platz 31, Munich 81377, Germany
H. Phillip Koeffler: Hematology/Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, California 90048, USA
Lee-Yung Shih: Chang Gung Memorial Hospital, Chang Gung University, 199 Tung Hwa North Rd, Taipei 105, Taiwan
Torsten Haferlach: Munich Leukemia Laboratory, Max-Lebsche-Platz 31, Munich 81377, Germany
Shigeru Chiba: Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki, 305-8571, Japan
Hiromitsu Nakauchi: Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
Satoru Miyano: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
Seishi Ogawa: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

Nature, 2011, vol. 478, issue 7367, 64-69

Abstract: 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.

Date: 2011
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DOI: 10.1038/nature10496

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