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Molecular mechanisms of clonal expansion in myelodysplasia

Research Project

Project/Area Number 24659458
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeSingle-year Grants
Research Field Hematology
Research InstitutionKyoto University (2013)
The University of Tokyo (2012)

Principal Investigator

SANADA Masashi  京都大学, 医学(系)研究科(研究院), 助教 (20529044)

Project Period (FY) 2012-04-01 – 2014-03-31
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords骨髄異形成症候群 / RNAスプライシング / 遺伝子変異 / 造血幹細胞 / 老化
Research Abstract

Frequent pathway mutations involving multiple components of the RNA splicing machinery is considered one of the most important genetic events in MDS. But the molecular mechanisms of these alterations in the pathogenesis of MDS are still unknown. In this study we investigated the functional role of these mutants in hematopoiesis using mice model that focused on clonal expansion of mutated cells. We analyzed the hematological phenotype of Sf3b1 hetero mice, and SF3B1 plays an important role in the regulation of hematopoietic stem cells (HSCs), whereas SF3B1 haploinsufficiency is not associated with the MDS phenotype. Loss of function mutation of TET2 are often co-existed in MDS cases with RNA spliceosome mutation, and that we performed the competitive stem cell transplantation using spliceosome mutant transduced HSCs from TET2 knockout mice or wild type mice. But there are no evidence of growth advantage of HSCs with RNA spliceosome mutation in spite of TET2 deletion in this model.

Report

(3 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Research-status Report
  • Research Products

    (27 results)

All 2014 2013 2012 Other

All Journal Article (18 results) (of which Peer Reviewed: 17 results,  Open Access: 2 results) Presentation (8 results) (of which Invited: 2 results) Book (1 results)

  • [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
      2013 Annual Research Report 2013 Final Research Report
    • Peer Reviewed / Open Access
  • [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 2013 Final 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 2013 Final 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] 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 2013 Final 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 2013 Final 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 2013 Final 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] 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] 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] Smap1 deficiency perturbs receptor trafficking and predisposes mice to myelodysplasia.2013

    • Author(s)
      Kon et al.
    • Journal Title

      J. Clin. Invest.

      Volume: 123 Issue: 3 Pages: 1123-1137

    • DOI

      10.1172/jci63711

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] EED mutants impair polycomb repressive complex 2 in myelodysplastic syndrome and related neoplasms2012

    • 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(12) Pages: 2557-60

    • Related Report
      2013 Final Research Report
  • [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 Research-status 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 Research-status 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 Research-status Report
    • Peer Reviewed
  • [Presentation] Role Of Sf3b1 On Hematopoiesis2013

    • Author(s)
      Matsunawa M, Yamamoto R, Sanada M, Sato A, Shiozawa Y, Yoshida K, Nagata Y, Kon A, Yoshizato T, Otsu M, Isono K, Koseki H, Nakauchi H, Ogawa S.
    • Organizer
      55th Annual Meeting of American Society of Hematology
    • Place of Presentation
      New Orleans
    • Year and Date
      2013-12-09
    • Related Report
      2013 Final Research Report
  • [Presentation] Role of Sf3b1 on Hematopoiesis2013

    • Author(s)
      Matsunawa M, Yamamoto R, Sanada M, et al.
    • Organizer
      第75回日本血液学会学術集会
    • Place of Presentation
      札幌
    • Year and Date
      2013-10-11
    • Related Report
      2013 Final Research Report
  • [Presentation] Functional Analysis of Cohesin Mutations in Myeloid Neoplasms2013

    • Author(s)
      Kon A, Sanada M, et al.
    • Organizer
      18th Congress of the European Hematology Association
    • Place of Presentation
      Stockholm
    • Year and Date
      2013-06-15
    • Related Report
      2013 Final Research Report
  • [Presentation] AMLにおけるゲノム異常2013

    • 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
  • [Presentation] Novel pathway mutations in myelodysplasia revealed by high-throughput sequencing technology.

    • Author(s)
      真田 昌
    • Organizer
      第71回日本癌学会学術総会
    • Place of Presentation
      札幌市
    • Related Report
      2012 Research-status Report
    • Invited
  • [Book] 「全エクソーム解析による骨髄異形成症候群の原因遺伝子の探索」別冊・医学のあゆみ「エクソーム解析―成果と将来」編集松本直通

    • Author(s)
      真田昌
    • Publisher
      医歯薬出版
    • Related Report
      2013 Final Research Report

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Published: 2013-05-31   Modified: 2019-07-29  

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