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Analysis on genetic basis of leukemia relapse and therapy resistance

Research Project

Project/Area Number 23249052
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionKyoto University (2013)
The University of Tokyo (2011-2012)

Principal Investigator

OGAWA SEISHi  京都大学, 医学(系)研究科(研究院), 教授 (60292900)

Project Period (FY) 2011-04-01 – 2014-03-31
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥47,970,000 (Direct Cost: ¥36,900,000、Indirect Cost: ¥11,070,000)
Fiscal Year 2013: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2012: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000)
Fiscal Year 2011: ¥20,280,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥4,680,000)
Keywords白血病 / 幹細胞 / リシーケンス / 遺伝子変異 / エピゲノム / 高速シーケンス / 再発 / 難治性白血病 / ゲノム / エクソーム解析 / エピゲノム解析 / 大量並列シーケンス / RNAスプライシング / 治療抵抗性 / 全ゲノム解析
Research Abstract

During the past two decades, significant advance has been made in therapeutics of leukemia. However, overall cure rates for many leukemia types have been less than 50%. In this study, to reveal genetic basis for relapsed or therapy-resistant leukemias, we performed comprehensive mutation studies for different types of leukemia, followed by targeted deep sequencing of newly identified as well as common mutational targets, using massively parallel sequencing in large cohorts of leukemias. We identified a number of new mutational targets, including multiple components of the cohesion complex and the RNA splicing machinery as well as SETBP1, DDX41, and DNA repair genes, many of which were associated with poor clinical outcomes. We further demonstrated that information of mutational status of multiple mutational targets could be used for better prediction of the clinical outcome of patients with AML, enabling their stratification for choice of therapeutics.

Report

(4 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Annual Research Report
  • 2011 Annual Research Report
  • Research Products

    (41 results)

All 2014 2013 2012 2011

All Journal Article (22 results) (of which Peer Reviewed: 22 results,  Open Access: 1 results) Presentation (17 results) (of which Invited: 4 results) Patent(Industrial Property Rights) (2 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] Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients2014

    • Author(s)
      Kihara R, S. Ogawa, S. (32/33) Naoe, T.
    • Journal Title

      Leukemia

      Volume: inpress Issue: 8 Pages: 1586-95

    • DOI

      10.1038/leu.2014.55

    • Related Report
      2013 Annual Research Report 2013 Final 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 2013 Final 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 2013 Final 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] 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] 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] Clonal selection in xenografted TAM recapitulates the evolutionary process of myeloid leukemia in Down syndrome.2013

    • Author(s)
      Saida, S., K. Watanabe, A. Sato-Otsubo, K. Terui, K. Yoshida, Y. Okuno, T. Toki, R. Wang, Y. Shiraishi, S. Miyano, I. Kato, T. Morishima, H. Fujino, K. Umeda, H. Hiramatsu, S. Adachi, E. Ito, S. Ogawa, M. Ito, T. Nakahata, and T. Heike.
    • Journal Title

      Blood

      Volume: 121 Issue: 21 Pages: 4377-4387

    • DOI

      10.1182/blood-2012-12-474387

    • Related Report
      2013 Final Research Report 2012 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 Final Research Report 2012 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 Final Research 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
      2013 Final Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] KIF5B-RET fusions in lung adenocarcinoma2012

    • Author(s)
      Takashi Kohno
    • Journal Title

      Nature Medicine

      Volume: 18 Issue: 3 Pages: 375-7

    • DOI

      10.1038/nm.2644

    • Related Report
      2013 Final Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Polycomb-Mediated Loss of miR-31 Activates NIK-dependent NF-κB Pathway in Adult T-cell Leukemia and Other Cancers2012

    • Author(s)
      Yamagishi M, Uchimaru K, et al.
    • Journal Title

      Cancer cell

      Volume: 21 Issue: 1 Pages: 121-135

    • DOI

      10.1016/j.ccr.2011.12.015

    • Related Report
      2013 Final Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel splicing-factor mutations in juvenile myelomonocytic leukemia2012

    • Author(s)
      Takita J, Yoshida K, Sanada M, Nishimura R, Okubo J, Motomura A, Hiwatari M, Oki K, Igarashi T, Hayashi Y, Ogawa S
    • Journal Title

      Leukemia

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Polycomb-Mediated Loss of miR-31 Activates NIK-Dependent NF-kap paB Pathway in Adult T Cell Leukemia and Other Cancers2011

    • Author(s)
      Yamagishi M, Nakano K, Miyake A, Yamochi T, Kagami Y, Tsutsiuni A, Matsuda Y, Sato-Otsubo A, Muto S, Utsunomiya A, Yamaguchi K, Uchimaru K, Ogawa S, Watanabe T
    • Journal Title

      Cancer cell

      Volume: 21 Pages: 121-135

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma2011

    • Author(s)
      Okubo J, Takita J, Chen Y, Oki K, Nishimura R, Kato M, Sanada M, Hiwatari M, Hayashi Y, Igarashi T, Ogawa S
    • Journal Title

      Oncogene

    • Related Report
      2013 Final Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Frequent pathway mutations of splicing machinery in myelodysplasia2011

    • Author(s)
      Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, Sato Y, Sato-Otsubo A, Kon A, Nagasaki M, Chalkidis G, Suzuki Y, Shiosaka M, Kawahata R, Yamaguchi T, Otsu M, Obara N, Sakata-Yanagimoto M, Ishiyama K, Mori H, Nolte F, Hofmann WK, Miyawaki S, Sugano S, Haferlach C, Koeffler HP, Shih LY, Haferlach T, Chiba S, Nakauchi H, Miyano S, Ogawa S
    • Journal Title

      Nature

      Volume: 478 Pages: 64-69

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] A nonsense mutation of IDH1 in myelodysplastic syndromes and related disorders2011

    • Author(s)
      Yoshida K, Sanada M, Kato M, Kawahata R, Matsubara A, Takita J, Shih LY, Mori H, Koeffler HP, Ogawa S
    • Journal Title

      Leukemia

      Volume: 25 Pages: 184-186

    • Related Report
      2013 Final Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hayashi Y.CBL mutations in infant acute lymphoblastic leukaemia2011

    • Author(s)
      Shiba N, Park MJ, Taki T, Takita J, Hiwatari M, Kanazawa T, Sotomatsu M, Ishii E, Arakawa H, Ogawa S
    • Journal Title

      Br J Haematol

      Volume: 156(5) Pages: 672-674

    • Related Report
      2013 Final Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Polycomb-Mediated Loss of miR-31 Activates NIK-Dependent NF-kap paB Pathway in Adult T Cell Leukemia and Other Cancers2011

    • Author(s)
      Yamagishi M, Nakano K, Miyake A, Yamochi T, Kagami Y, Tsutsiuni A, Matsuda Y, Sato-Otsubo A, Muto S, Utsunomiya A, Yamaguchi K, Uchimaru K, Ogawa S, Watanabe T
    • Journal Title

      Cancer cell.

      Volume: 21 Pages: 121-135

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Frequent pathway mutations of splicing machinery in myelodysplasia2011

    • Author(s)
      Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, Sato Y, Sato-Otsubo A, Kon A, Nagasaki M, Chalkidis G, Suzuki Y, Shiosaka M, Kawahata R, Yamaguchi T, Otsu M, Obara N, Sakata-Yanagimoto M, Ishiyama K, Mori H, Nolte F, Hofmann WK, Miyawaki S, Sugano S, Haferlach C, Koeffler HP, Shih LY, Haferlach T, Chiba S, Nakauchi H, Miyano S, Ogawa S
    • Journal Title

      Nature.

      Volume: 478 Pages: 64-69

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Presentation] Recurrent somatic SETBP1 mutations in myeloid neoplasms2013

    • Author(s)
      Ayana Kon, Ogawa S., et al
    • Organizer
      第72回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2013-10-05
    • Related Report
      2013 Annual Research Report 2013 Final Research Report
  • [Presentation] Recurrent somatic SETBP1 mutations in myeloid neoplasms2013

    • Author(s)
      Ayana Kon, Ogawa S., et al
    • Organizer
      第75回日本血液学会学術集会
    • Place of Presentation
      北海道
    • Year and Date
      2013-10-01
    • Related Report
      2013 Annual Research Report 2013 Final Research Report
  • [Presentation] Comprehensive genome analysis of pediatric myeloid neoplasms2013

    • Author(s)
      Ogawa S., et al
    • Organizer
      18th Congress of EHA
    • Place of Presentation
      Stockholm(Sweden)
    • Year and Date
      2013-06-15
    • Related Report
      2013 Annual Research Report 2013 Final Research Report
  • [Presentation] RE-CLASSIFICATION OF ADULT ACUTE MYELOID LEUKEMIA BASED ON THE COMPREHENSIVE GENETIC ANALYSIS2013

    • Author(s)
      Kihara R, Ogawa S., et al
    • Organizer
      18th Congress of EHA
    • Place of Presentation
      Stockholm(Sweden)
    • Year and Date
      2013-06-14
    • Related Report
      2013 Final Research Report
  • [Presentation] Recent advance in molecular genetics of MDS as revealed by massively parallel sequencing2013

    • Author(s)
      Ogawa S., et al
    • Organizer
      18th Congress of EHA
    • Place of Presentation
      Stockholm(Sweden)
    • Year and Date
      2013-06-13
    • Related Report
      2013 Annual Research Report 2013 Final Research Report
  • [Presentation] Recurrent pathway mutations of multiple components of cohesin complex in myeloid neoplasms2013

    • Author(s)
      Ayana Kon, Ogawa S., et al
    • Organizer
      AACR Annual meeting
    • Place of Presentation
      Washington, DC (USA)
    • Year and Date
      2013-04-09
    • Related Report
      2013 Final Research Report
  • [Presentation] Genetic analysis of myelodysplastic syndromes2013

    • Author(s)
      Seishi Ogawa
    • Organizer
      The 2013 Joint Symposium : multi-Omics in KSBMB WinterWorkshop
    • Place of Presentation
      High-One Resort, (Korea )
    • Year and Date
      2013-01-16
    • Related Report
      2013 Final Research Report
  • [Presentation] Recurrent pathway mutations of multiple components of cohesin complex in myeloid neoplasms2013

    • Author(s)
      Ayana Kon, Ogawa S. et al.
    • Organizer
      AACR Annual meeting 2013
    • Place of Presentation
      Washington, DC (USA)
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] RE-CLASSIFICATION OF ADULT ACUTE MYELOID LEUKEMIA BASED ON THE COMPREHENSIVE GENETIC ANALYSIS.2013

    • Author(s)
      Kihara R, Ogawa S. et al.
    • Organizer
      18th Congress of EHA
    • Place of Presentation
      Stockholm(Sweden)
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Landscape of genetic lesions in 944 patients with Myelodysplastic syndromes2013

    • Author(s)
      永田安伸, 小川誠司, et al.
    • Organizer
      第75回日本血液学会学術集会
    • Place of Presentation
      北海道
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Genetic analysis of myelodysplastic syndromes2013

    • Author(s)
      Seishi Ogawa
    • Organizer
      The 2013 Joint Symposium: multi-Omics in KSBMB Winter Workshop
    • Place of Presentation
      High-One Resort, Korea
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] Pathway Mutations in the Splicing Machinery in Myeloid Neoplasms2012

    • Author(s)
      Seishi Ogawa
    • Organizer
      2012 ASH Annual Meeting and Exposition
    • Place of Presentation
      Atlanta, USA
    • Year and Date
      2012-12-08
    • Related Report
      2013 Final Research Report 2012 Annual Research Report
  • [Presentation] Genetic analysis of myelodneoplasms in childhood2012

    • Author(s)
      Seishi Ogawa
    • Organizer
      Cambridge Research Institute Annual International Symposium
    • Place of Presentation
      Cambridge, UK
    • Year and Date
      2012-11-02
    • Related Report
      2013 Final Research Report 2012 Annual Research Report
  • [Presentation] Deregulated RNA splicing Machinery in Myelodysplastic Syndromes2012

    • Author(s)
      Ogawa S.
    • Organizer
      2012 AACB meeting
    • Place of Presentation
      Chicago, IL, USA(招待講演)
    • Year and Date
      2012-03-31
    • Related Report
      2011 Annual Research Report
  • [Presentation] Novel pathway mutations in myelodysplasia2012

    • Author(s)
      Ogawa S.
    • Organizer
      Bone Marrow Failure Disease Scientific Symposium
    • Place of Presentation
      Bethesda, ML, USA(招待講演)
    • Year and Date
      2012-03-22
    • Related Report
      2011 Annual Research Report
  • [Presentation] Genetic analysis of myelodysplastic syndromes and related disorders2011

    • Author(s)
      Ogawa S.
    • Organizer
      US-JAPAN Cancer Workshop
    • Place of Presentation
      Bethesda, ML, USA(招待講演)
    • Year and Date
      2011-10-25
    • Related Report
      2011 Annual Research Report
  • [Presentation] Genetic analysis of myelodysplastic syndromes and related disorders2011

    • Author(s)
      Ogawa S
    • Organizer
      US-JAPAN CONFERENCE ON INFLAMM ATION, DIABETES AND CANCER
    • Place of Presentation
      Duarte, CA, USA(招待講演)
    • Year and Date
      2011-08-05
    • Related Report
      2011 Annual Research Report
  • [Patent(Industrial Property Rights)] 骨髄異形成症候群または骨髄性腫瘍素因の評価方法, そのポリペプチド及び抗体2011

    • Inventor(s)
      小川誠司, 真田昌, 吉田健一
    • Industrial Property Rights Holder
      国立大学法人東京大学
    • Industrial Property Number
      2011-169662
    • Filing Date
      2011-08-02
    • Related Report
      2013 Final Research Report
  • [Patent(Industrial Property Rights)] 骨髄異形成症候群または骨髄性腫瘍素因の評価方法、そのポリペプチド及び抗体2011

    • Inventor(s)
      小川誠司、真田昌、吉田健一
    • Industrial Property Rights Holder
      国立大学法人東京大学
    • Industrial Property Number
      2011-169662
    • Filing Date
      2011-08-02
    • Related Report
      2011 Annual Research Report

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Published: 2011-04-06   Modified: 2019-07-29  

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