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Frequent pathway mutations of splicing machinery in myelodysplasia

Author

Listed:
  • 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
    National University of Singapore, Cancer Science Institute of Singapore, 28 Medical Drive, Singapore 117456, Singapore)

  • 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
    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)

  • 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
    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)

  • Seishi Ogawa

    (Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan)

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.

Suggested Citation

  • 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 & M, 2011. "Frequent pathway mutations of splicing machinery in myelodysplasia," Nature, Nature, vol. 478(7367), pages 64-69, October.
    • Handle: RePEc:nat:nature:v:478:y:2011:i:7367:d:10.1038_nature10496
    DOI: 10.1038/nature10496
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    Cited by:

    1. Tariq Kewan & Arda Durmaz & Waled Bahaj & Carmelo Gurnari & Laila Terkawi & Hussein Awada & Olisaemeka D. Ogbue & Ramsha Ahmed & Simona Pagliuca & Hassan Awada & Yasuo Kubota & Minako Mori & Ben Ponvi, 2023. "Molecular patterns identify distinct subclasses of myeloid neoplasia," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Jorge Mata-Garrido & Yao Xiang & Yunhua Chang-Marchand & Caroline Reisacher & Elisabeth Ageron & Ida Chiara Guerrera & Iñigo Casafont & Aurelia Bruneau & Claire Cherbuy & Xavier Treton & Anne Dumay & , 2022. "The Heterochromatin protein 1 is a regulator in RNA splicing precision deficient in ulcerative colitis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. David Rombaut & Carine Lefèvre & Tony Rached & Sabrina Bondu & Anne Letessier & Raphael M. Mangione & Batoul Farhat & Auriane Lesieur-Pasquier & Daisy Castillo-Guzman & Ismael Boussaid & Chloé Friedri, 2024. "Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    4. Muran Xiao & Shinji Kondo & Masaki Nomura & Shinichiro Kato & Koutarou Nishimura & Weijia Zang & Yifan Zhang & Tomohiro Akashi & Aaron Viny & Tsukasa Shigehiro & Tomokatsu Ikawa & Hiromi Yamazaki & Mi, 2023. "BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    5. Nikolai Schleussner & Pierre Cauchy & Vedran Franke & Maciej Giefing & Oriol Fornes & Naveen Vankadari & Salam A. Assi & Mariantonia Costanza & Marc A. Weniger & Altuna Akalin & Ioannis Anagnostopoulo, 2023. "Transcriptional reprogramming by mutated IRF4 in lymphoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Mariela Cortés-López & Laura Schulz & Mihaela Enculescu & Claudia Paret & Bea Spiekermann & Mathieu Quesnel-Vallières & Manuel Torres-Diz & Sebastian Unic & Anke Busch & Anna Orekhova & Monika Kuban &, 2022. "High-throughput mutagenesis identifies mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    7. Patricia González-Rodríguez & Daniel J. Klionsky & Bertrand Joseph, 2022. "Autophagy regulation by RNA alternative splicing and implications in human diseases," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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