• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Molecular mechanisms of blast crisis transition and maintenance of leukemic stem cells in chronic myelogenous leukemia

Research Project

Project/Area Number 23791074
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Hematology
Research InstitutionThe University of Tokyo

Principal Investigator

NAKAHARA Fumio  東京大学, 医科学研究所, 助教 (80581181)

Project Period (FY) 2011 – 2012
Project Status Completed (Fiscal Year 2012)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2011: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Keywords白血病 / 白血病幹細胞 / 慢性骨髄性白血病 / 急性転化
Research Abstract

High levels of Hes1 expression are frequently found in BCR-ABL-positive chronic myelogenous leukemia in blast crisis (CML-BC). In mouse bone marrow transplantation (BMT) models, co-expression of BCR-ABL and Hes1 induces CML-BC-like disease; however the underlying mechanism remained elusive. Here, based on gene expression analysis, we show that MMP-9 is upregulated by Hes1 in common myeloid progenitors (CMPs). Analysis of promoter activity demonstrated that Hes1 upregulated MMP-9 by activating NF-kB. Analysis of 20 samples from CML-BC patients showed that MMP-9 was highly expressed in three, with two exhibiting high levels of Hes1 expression. Interestingly, MMP-9 deficiency impaired the cobblestone area-forming ability of CMPs expressing BCR-ABL and Hes1 that were in conjunction with a stromal cell layer. In addition, these CMPs secreted MMP-9, promoting the release of soluble Kit-ligand (sKitL) from stromal cells, thereby enhancing proliferation of the leukemic cells. In accordance, mice transplanted with CMPs expressing BCR-ABL and Hes1 exhibited high levels of sKitL as well as MMP-9 in the serum. Importantly, MMP-9 deficiency impaired the development of CML-BC-like disease induced by BCR-ABL and Hes1 in mouse BMT models. Thus, Hes1 promotes the development of CML-BC, partly through MMP-9 upregulation in leukemic cells.

Report

(3 results)
  • 2012 Annual Research Report   Final Research Report ( PDF )
  • 2011 Research-status Report
  • Research Products

    (16 results)

All 2013 2012 2011

All Journal Article (14 results) (of which Peer Reviewed: 4 results) Presentation (2 results)

  • [Journal Article] Human CD300C Delivers an Fc Receptor-gamma-dependent Activating Signal in Mast Cells and Monocytes and Differs from CD300A in Ligand Recognition2013

    • Author(s)
      Takahashi M, Izawa K, Kashiwakura J, Yamanishi Y, Enomoto Y, Kaitani A, Maehara A, Isobe M, Ito S, Matsukawa T, Nakahara F, Oki T, Kajikawa M, Ra C, Okayama Y, Kitamura T and Kitaura J
    • Journal Title

      J Biol Chem

      Volume: 288 Pages: 7662-75

    • Related Report
      2012 Final Research Report
  • [Journal Article] The receptor LMIR3 negatively regulates mast cell activation and allergic responses by binding to extracellular ceramide2012

    • Author(s)
      Izawa K, Yamanishi Y, Maehara A, Takahashi M, Isobe M, Ito S, Kaitani A, Matsukawa T, Matsuoka T, Nakahara F,Oki T, Kiyonari H, Abe T, Okumura K, Kitamura T and Kitaura J
    • Journal Title

      Immunity

      Volume: 37 Pages: 827-39

    • Related Report
      2012 Final Research Report
  • [Journal Article] Upregulation of CD200R1 in lineage-negative leukemic cells is characteristic of AML1-ETO-positive leukemia in mice2012

    • Author(s)
      Kagiyama Y, Kitaura J, Togami K, Uchida T, Inoue D, Matsukawa T, Izawa K, Kawabata KC, Komeno Y, Oki T, Nakahara F, Sato K, Aburatani H and Kitamura T
    • Journal Title

      Int J Hematol

      Volume: 96 Pages: 638-48

    • NAID

      10031126762

    • Related Report
      2012 Final Research Report
  • [Journal Article] Molecular mechanisms underlying leukemic transformation of myelodysplastic syndromes (MDS) and chronic myelogenous leukemia (CML)2012

    • Author(s)
      Kitamura T, Watanabe-Okochi N, InoueD, Togami K, Uchida T, Kagiyama Y, Kawabata K, Chiba S, Harada Y, Harada H, Kitaura J and Nakahara F
    • Journal Title

      Rinsho Ketsueki

      Volume: 53 Pages: 734-9

    • NAID

      130004501712

    • Related Report
      2012 Final Research Report
  • [Journal Article] A soluble form of LMIR5/CD300b amplifies lipopolysaccharide-induced lethal inflammation in sepsis2012

    • Author(s)
      Yamanishi Y, Takahashi M, Izawa K, Isobe M, Ito S, Tsuchiya A, Maehara A, Kaitani A, Uchida T, Togami K, Enomoto Y, Nakahara F, Oki T, Kajikawa M, Kurihara H, Kitamura T and Kitaura J
    • Journal Title

      J Immuno

      Volume: l189 Pages: 1773-9

    • Related Report
      2012 Final Research Report
  • [Journal Article] Fyn is not essential for Bcr-Abl-induced leukemogenesis in mouse bone marrow transplantation models2012

    • Author(s)
      Doki N, Kitaura J, Uchida T, Inoue D, Kagiyama Y, Togami K, Isobe M, Ito S, Maehara A, Izawa K, Kato N, Oki T, Harada Y, Nakahara F, Harada H and Kitamura T
    • Journal Title

      Int JHematol

      Volume: 95 Pages: 167-75

    • NAID

      10030267340

    • Related Report
      2012 Final Research Report
  • [Journal Article] Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations in T-cell leukemogenesis.2012

    • Author(s)
      Oki T, Kitaura J, Watanabe-Okochi N, Nishimura K, Maehara A, Uchida T, Komeno Y, Nakahara F, Harada Y, Sonoki T, Harada H and Kitamura T
    • Journal Title

      Leukemia

      Volume: 26 Pages: 1038-45

    • Related Report
      2012 Final Research Report
  • [Journal Article] Transforming growth factor-beta-stimulated clone-22 is a negative-feedback regulator of Ras / Raf signaling: Implications for tumorigenesis2012

    • Author(s)
      Nakamura M, Kitaura J, Enomoto Y, Lu Y, Nishimura K, Isobe M, Ozaki K, Komeno Y, Nakahara F, Oki T, Kume H, Homma Y and Kitamura T
    • Journal Title

      Cancer Sci

      Volume: 103 Pages: 26-33

    • Related Report
      2012 Final Research Report
  • [Journal Article] Identification of RHOXF2 (PEPP2) as a cancer-promoting gene by expression cloning2012

    • Author(s)
      Shibata-Minoshima F, Oki T, Doki N,Nakahara F, Kageyama S, Kitaura J, Fukuoka J and Kitamura T
    • Journal Title

      Int J Oncol

      Volume: 40 Pages: 93-8

    • Related Report
      2012 Final Research Report
  • [Journal Article] The receptor LMIR3 negatively regulates mast cell activation and allergic responses by binding to extracellular ceramide.2012

    • Author(s)
      Izawa K, Yamanishi Y, Maehara A, Takahashi M, Isobe M, Ito S, Kaitani A, Matsukawa T, Matsuoka T, Nakahara F, Oki T, Kiyonari H, Abe T, 0kumura K, Kitamura T, Kitaura J.
    • Journal Title

      Immunity

      Volume: 16;37(5) Issue: 5 Pages: 827-39

    • DOI

      10.1016/j.immuni.2012.08.018

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Upregulation of CD200R1 in lineage-negative leukemic cells is characteristic of AML1-ETO-positive leukemia in mice.2012

    • Author(s)
      Kagiyama Y, Kitaura J, Togami K, Uchida T, Inoue D, Matsukawa T, Izawa K, Kawabata KC, Komeno Y, Oki T, Nakahara F, Sato K, Aburatani H, Kitamura T.
    • Journal Title

      Int J Hematol.

      Volume: 96(5) Issue: 5 Pages: 638-48

    • DOI

      10.1007/s12185-012-1207-6

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Molecular mechanisms underlying leukemic transformation of myelodysplastic syndromes (MDS) and chronic myelogenous leukemia (CML)2012

    • Author(s)
      Kitamura T
    • Journal Title

      Rinsho Ketsueki

      Volume: 53(8) Pages: 734-39

    • Related Report
      2012 Annual Research Report
  • [Journal Article] Fyn is not essential for Bcr-Ab1-induced leukemogenesis in mouse bone marrow transplantation models2012

    • Author(s)
      Doki N, Kitaura J, Inoue D, Kato N, Kagiyama Y, Uchida T, Togami K, Isobe M, Ito S, Maehara A, Izawa K, Oki T, Harada Y, Nakahara F, Harada H, Kitamura T
    • Journal Title

      Int J Hematol

      Volume: 95(2) Issue: 2 Pages: 167-175

    • DOI

      10.1007/s12185-011-0994-5

    • Related Report
      2012 Annual Research Report 2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations in T-cell leukemogenesis2012

    • Author(s)
      Oki T, Kitaura J, Watanabe-Okochi N, Nishimura K, Maehara A, Uchida T, Komeno Y, Nakahara F, Harada Y, Sonoki T, Harada H, Kitamura T
    • Journal Title

      Leukemia

      Volume: (in press) Issue: 5 Pages: 1038-1045

    • DOI

      10.1038/leu.2011.328

    • Related Report
      2012 Annual Research Report 2011 Research-status Report
    • Peer Reviewed
  • [Presentation] Molecular mechanisms of blast crisis in chronic myelogenous leukemia caused by upregulation of Hes12012

    • Author(s)
      Fumio Nakahara, Toshio Kitamura
    • Organizer
      第74回日本血液学会学術集会
    • Place of Presentation
      国立京都国際会館
    • Year and Date
      2012-10-20
    • Related Report
      2012 Annual Research Report 2012 Final Research Report
  • [Presentation] Molecular mechanisms of blast crisis in chronic2011

    • Author(s)
      第70回日本癌学会学術総会
    • Organizer
      日本癌学会(招待講演)
    • Place of Presentation
      名古屋国際会議場
    • Related Report
      2011 Research-status Report

URL: 

Published: 2011-08-05   Modified: 2019-07-29  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi