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Molecular pathogenesis of spliceosome mutations in MDS

Research Project

Project/Area Number 24390242
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Hematology
Research InstitutionKyoto University (2013-2014)
The University of Tokyo (2012)

Principal Investigator

MASASHI Sanada  京都大学, 医学(系)研究科(研究院), 研究員 (20529044)

Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
Fiscal Year 2014: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2013: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2012: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
Keywords骨髄異形成症候群 / RNAスプライシング / 造血幹細胞 / MDS / RNAシーケンス / モデルマウス / がん / ゲノム / 遺伝学 / マウスモデル / 遺伝子操作マウス / レトロウィルス
Outline of Final Research Achievements

Frequent mutation in RNA splicing factors is a cardinal feature of myelodysplastic syndromes. To understand their molecular mechanisms, we constructed model mice for these alterations in this study. In Sf3b1 hetero knockout mice and Srsf2 mutant conditional knock-in mice the number of hematopoietic stem cells are lower than those in wild type mice, and these repopulation capacities are also reduced. And RNA sequencing of hematopoietic stem/ progenitor cells from Srsf2 mutated mice showed abnormal exon usages in many genes. Thus, in conclusion, these findings suggest that RNA spliceosome mutations lead to deregulated hematopoietic stem cell functions likely due to abnormal RNA splicing.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • Research Products

    (28 results)

All 2015 2014 2013 2012 Other

All Journal Article (19 results) (of which Peer Reviewed: 19 results,  Open Access: 4 results) Presentation (8 results) (of which Invited: 1 results) Book (1 results)

  • [Journal Article] Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome.2015

    • Author(s)
      Madan V, Kanojia D, Li J, Okamoto R, Sato-Otsubo A, Kohlmann A, Sanada M, Grossmann V, Sundaresan J, Shiraishi Y, Satoru M, Thol F, Ganser A, Yang H, Haferlach T, Ogawa S, Koeffler HP
    • Journal Title

      Nature Commun.

      Volume: 6 Issue: 1 Pages: 6042-6042

    • DOI

      10.1038/ncomms7042

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Haploinsufficiency of Sf3b1 leads to compromised stem cell function but not to myelodysplasia.2014

    • Author(s)
      Matsunawa M, Yoshida K
    • Journal Title

      Leukemia

      Volume: (Epub ahead of print) Issue: 9 Pages: 1-7

    • DOI

      10.1038/leu.2014.73

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome.2014

    • Author(s)
      7.Sato Y, Maekawa S, Ishii R, Sanada M, Morikawa T, Shiraishi Y, Yoshida K, Nagata Y, Sato-Otsubo A, Yoshizato T, Suzuki H, Shiozawa Y, Kataoka K, Kon A, Aoki K, Chiba K, Tanaka H, Kume H, Miyano S, Fukayama M, Nureki O, Homma Y, Ogawa S.
    • Journal Title

      Science

      Volume: 344 Issue: 6186 Pages: 917-920

    • DOI

      10.1126/science.1252328

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Recurrent genetic defects on chromosome 7q in myeloid neoplasms.2014

    • Author(s)
      10.Hosono N, Makishima H, Jerez A, Yoshida K, Przychodzen B, McMahon S, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Sanada M, Gómez-Seguí I, Verma AK, McDevitt MA, Sekeres MA, Ogawa S, Maciejewski JP.
    • Journal Title

      Leukemia

      Volume: 28 Issue: 6 Pages: 1348-1351

    • DOI

      10.1038/leu.2014.25

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Somatic RHOA mutation in angioimmunoblastic T cell lymphoma.2014

    • Author(s)
      Sakata-Yanagimoto M, Yoshida K
    • Journal Title

      Nature Genet.

      Volume: 46 Issue: 2 Pages: 171-175

    • DOI

      10.1038/ng.2872

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Landscape of genetic lesions in 944 patients with myel odysplastic syndromes.2014

    • Author(s)
      Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, Schnittger S, Sanada M, Kon A, Alpermann T, Yoshida K, Roller A, Nadarajah N, Shiraishi Y, Shiozawa Y, Chiba K, Tanaka H, Koeffler HP, Klein HU, Dugas M, Aburatani H, Kohlmann A, Miyano S, Haferlach C, Kern W, Ogawa S.
    • Journal Title

      Leukemia

      Volume: 28(2) Issue: 2 Pages: 241-7

    • DOI

      10.1038/leu.2013.336

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Clonal leukemic evolution in myelodysplastic syndromes with TET2 and IDH1/2 mutations.2014

    • Author(s)
      Lin, T. L. Nagata, Y. Kao, H. W. Sanada, M. Okuno, Y. Huang, C. F. Liang, D. C. Kuo, M. C. Lai, C. L. Lee, E. H. Shih, Y. S. Tanaka, H. Shiraishi, Y. Chiba, K. Lin, T. H. Wu, J. H. Miyano, S. Ogawa, S. Shih, L. Y.
    • Journal Title

      Haematologic

      Volume: 99 Issue: 1 Pages: 28-36

    • DOI

      10.3324/haematol.2013.091249

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders.2013

    • Author(s)
      Muto T, Sashida G, Oshima M, Wendt GR, Mochizuki-Kashio M, Nagata Y, Sanada M, Miyagi S, Saraya A, Kamio A, Nagae G, Nakaseko C, Yokote K, Shimoda K, Koseki H, Suzuki Y, Sugano S, Aburatani H, Ogawa S, Iwama A.
    • Journal Title

      The Journal of Experimental Medicine

      Volume: 210(12) Issue: 12 Pages: 2627-39

    • DOI

      10.1084/jem.20131144

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] BCOR and BCORL1 mutations in myelodysplastic synd romes and related disorders.2013

    • Author(s)
      Damm F, Chesnais V, Nagata Y, Yoshida K, Scourzic L, Okuno Y, Itzykson R, Sanada M, Shiraishi Y, Gelsi-Boyer V, Renneville A, Miyano S, Mori H, Shih LY, Park S, Dreyfus F, Guerci-Bresler A, Solary E, Rose C, Cheze S, Prebet T, Vey N, Legentil M, Duffourd Y, de Botton S, Preudhomme C, Birnbaum D, Bernard OA, Ogawa S, Fontenav M, Kosmider O.
    • Journal Title

      Blood

      Volume: 122(18) Issue: 18 Pages: 3169-77

    • DOI

      10.1182/blood-2012-11-469619

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms.2013

    • Author(s)
      Kon A, Yoshida K
    • Journal Title

      Nature Genet.

      Volume: 45 Issue: 10 Pages: 1232-1237

    • DOI

      10.1038/ng.2731

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The landscape of somatic mutations in Down syndrome-related myeloid disorders.2013

    • Author(s)
      Yoshida K
    • Journal Title

      Nature Genet.

      Volume: 45 Issue: 11 Pages: 1293-1200

    • DOI

      10.1038/ng.2759

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Somatic SETBP1 mutations in myeloid malignancies.2013

    • Author(s)
      Makishima H, Yoshida K
    • Journal Title

      Nature Genet.

      Volume: 45 Issue: 8 Pages: 942-946

    • DOI

      10.1038/ng.2696

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] An empirical Bayesian framework for somatic mutation detection from cancer genome sequencing data2013

    • Author(s)
      Yuichi Shiraishi
    • Journal Title

      Nucleic Acid Research

      Volume: 41 Issue: 7 Pages: e89-e89

    • DOI

      10.1093/nar/gkt126

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia.2013

    • Author(s)
      Sakaguchi H, Yoshida K
    • Journal Title

      Nature Genet.

      Volume: 46 Issue: 8 Pages: 937-941

    • DOI

      10.1038/ng.2698

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Deep sequencing in cancer research.2013

    • Author(s)
      Yoshida K, Sanada M, Ogawa S.
    • Journal Title

      Jpnj clin oncol.

      Volume: 432 Issue: 2 Pages: 110-5

    • DOI

      10.1093/jjco/hys206

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ACTN1 Mutations Cause Congenital Macrothrombocytopenia2013

    • Author(s)
      國島伸治、吉田健一
    • Journal Title

      Am J Hum Genet

      Volume: 92 Issue: 3 Pages: 431-438

    • DOI

      10.1016/j.ajhg.2013.01.015

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] EED mutants impair polycomb repressive complex 2 in myelodysplastic syndrome and related neoplasms.2012

    • Author(s)
      Ueda T, Sanada M, Matsui H, Yamasaki N, Honda ZI, Shih LY, Mori H, Inaba T, Ogawa S, Honda H.
    • Journal Title

      Leukemia.

      Volume: 26 Issue: 12 Pages: 2557-60

    • DOI

      10.1038/leu.2012.146

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel splicing-factor mutations in juvenile myelomonocytic leukemia2012

    • Author(s)
      滝田順子、吉田健一
    • Journal Title

      Leukemia

      Volume: 26 Issue: 8 Pages: 1879

    • DOI

      10.1038/leu.2012.45

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Genome-wide analysis of myelodysplastic syndromes.2012

    • Author(s)
      Sanada M, Ogawa S
    • Journal Title

      Curr Pharm Des

      Volume: 18 Pages: 3163-3169

    • NAID

      40019688461

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Presentation] Comprehensive Analysis of Alternative RNA Splicing in Myelodysplastic Syndrome2014

    • Author(s)
      Yusuke Shiozawa, Sato Sato-Otsubo, Anna Gallì, Kenichi Yoshida, Tetsuichi Yoshizato, Yusuke Sato, Keisuke Kataoka,Masashi Sanada,Yuichi Shiraishi, Kenichi Chiba, Satoru Miyano, Luca Malcovati, Mario Cazzola, and Seishi Ogawa
    • Organizer
      56th American Society of Hematology 2014 Annual Meeting
    • Place of Presentation
      San Francisco, USA
    • Year and Date
      2014-12-05 – 2014-12-09
    • Related Report
      2014 Annual Research Report
  • [Presentation] ZRSR2 Mutations Cause Dysregulated RNA Splicing in MDS2014

    • Author(s)
      Vikas Madan, Deepika Kanojia, Li Jia, Ryoko Okamoto, Aiko Sato-Otsubo, Alexander Kohlmann, Masashi Sanada, Vera Grossmann, Janani Sundaresan, Yuichi Shiraishi, Satoru Miyano, Felicitas Thol, Arnold Ganser, Henry Yang, Torsten Haferlach, Seishi Ogawa, and H. Phillip Koeffler
    • Organizer
      56th American Society of Hematology 2014 Annual Meeting
    • Place of Presentation
      San Francisco, USA
    • Year and Date
      2014-12-05 – 2014-12-09
    • Related Report
      2014 Annual Research Report
  • [Presentation] SF3B1 PLAYS AN IMPORTANT ROLE IN THE REGULATION OF HEMATOPOIETIC STEMS CELLS, BUT HAPLOINSUFFICIENCY OF SF3B1 MAY NOT BE SOLELY RESPONSIBLE FOR MYELODYSPLASIA2014

    • Author(s)
      Manabu Matsunawa, Ryo Yamamoto, Masashi Sanada, Ayana Kon, Aiko Sato-Otsubo, Yusuke Shiozawa, Kenichi Yoshida, Yasunobu Nagata, Tetsuichi Yoshizato, Makoto Otsu, Kyoichi Isono, Haruhiko Koseki, Hiromitsu Nakauchi, Seishi Ogawa
    • Organizer
      The 19th Congress of European Hematology Association
    • Place of Presentation
      Milan, Italy
    • Year and Date
      2014-06-12 – 2014-06-15
    • Related Report
      2014 Annual Research Report
  • [Presentation] Novel pathway mutations in myelodysplasia revealed by high-throughput sequencing technology.2012

    • Author(s)
      真田昌
    • Organizer
      第71回日本癌学会学術総会
    • Place of Presentation
      札幌市(招待講演)
    • Year and Date
      2012-09-20
    • Related Report
      2012 Annual Research Report
  • [Presentation] AMLにおけるゲノム異常

    • Author(s)
      眞田 昌
    • Organizer
      第75回日本血液学会学術集会
    • Place of Presentation
      札幌
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Role Of Sf3b1 On Hematopoiesis

    • Author(s)
      Manabu Matsunawa, Ryo Yamamoto, Masashi Sanada, Aiko Sato, Yusuke Shiozawa, Kenichi Yoshida, Yasunobu Nagata, Ayana Kon, Tetsuichi Yoshizato, Makoto Otsu, Kyoichi Isono, Haruhiko Koseki, Hiromitsu Nakauchi, and Seishi Ogawa
    • Organizer
      55th Annual Meeting of American Society of Hematology
    • Place of Presentation
      New Orleans
    • Related Report
      2013 Annual Research Report
  • [Presentation] FUNCTIONAL ANALYSIS OF COHESIN MUTATIONS IN MYELOID NEOPLASMS

    • Author(s)
      Ayana Kon, Masashi Sanada, et al. (2/20)
    • Organizer
      18th Congress of the European Hematology Association
    • Place of Presentation
      Stockholm
    • Related Report
      2013 Annual Research Report
  • [Presentation] Role Of Sf3b1 On Hematopoiesis

    • Author(s)
      Manabu Matsunawa, Ryo Yamamoto, Masashi Sanada, Aiko Sato, Yusuke Shiozawa, Kenichi Yoshida, Yasunobu Nagata, Ayana Kon, Tetsuichi Yoshizato, Makoto Otsu, Kyoichi Isono, Haruhiko Koseki, Hiromitsu Nakauchi, and Seishi Ogawa
    • Organizer
      第75回日本血液学会学術集会
    • Place of Presentation
      札幌
    • Related Report
      2013 Annual Research Report
  • [Book] 医学のあゆみVol.249 No.10特集 がんゲノム研究の進歩ー網羅的解析からの知見2014

    • Author(s)
      眞田 昌
    • Total Pages
      129
    • Publisher
      医歯薬出版
    • Related Report
      2014 Annual Research Report

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Published: 2012-04-24   Modified: 2019-07-29  

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