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2004 Fiscal Year Final Research Report Summary

Molecular mechanisms of leukemogenesis and pathogenesis in adult T-cell leukemia

Research Project

Project/Area Number 12213057
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionKyoto University

Principal Investigator

MATSUOKA Kasao  Institute for Virus Research, Professor, ウイルス研究所, 教授 (10244138)

Project Period (FY) 2000 – 2004
KeywordsAdult T-cell leukemia / Retrovirus / Oncogenesis / HTLV-I / Methylation / Leukemogenesis
Research Abstract

After infection of human T-cell leukemia virus type I (HTLV-I), there is a long latent period before the onset of adult T-cell leukemia (ATL). I have studied the molecular mechanisms of leukemogenesis, and pathogenesis in ATL.
1) DNA methylation was first detected in the exon of p16 gene, and then it progressed to the promoter region. When the promoter region was methylated, the transcription of p16 gene was silenced. We found that DNA methylation of 5'-long terminal repeat (LTR) silenced the viral gene transcription. Within provirus, DNA methylation first occurred in the internal regions, such as gag, pol and env regions, and then spread to 5' and 3' directions. We isolated the aberrant methylated DNA regions in ATL cells by Methylated CpG island amplification/representative difference assay (MCA/RDA). MEL1S gene was identified as hypomethylated one in ATL cells. Aberrant expression of MEL1S gene was observed in ATL cells, which enabled ATL cells resistant to TGF-β. Therefore, MEL1S ex … More pression is considered to be one of mechanisms to confer the resistance to TGF-β. On the other hand, KLF4 and EGR3 genes were found to be hypermethylated in ATL cells. Silenced EGR3 gene transcription results in loss of Fas ligand expression, which enables ATL cells to escape from Fas-Fas ligand induced apoptosis.
2) ATL cells from hypercalcemic patients were found to express RANK ligand on their surfaces and produce M-CSF. RANK ligand and M-CSF have shown to co-operatively induce the differentiation of hematopoietic precursor cells into osteolcast. ATL cells from hypercalcemic patients could induce the differentiation to osteoclast in vitro.
3) Immunodeficiet state is observed in HTLV-I infected individuals and ATL patients. We analyzed the naive and memory T-cell subpopulation among HTLV-I carriers and ATL patients, and found that the number of naive T-cell decreased in HTLV-I infected individuals. Since T-cell receptor excision circles were decreased in HTLV-I infected individuals, decreased naive T-cell is thought to be due to suppressed production in the thymus.
4) Tax expression is frequently lost in ATL cells. We identified three mechanisms in inactivation of Tax expression : 1) genetic changes of tax gene, 2) DNA methylation of 5'-LTR and 3) deletion of 5'-LTR. Less

  • Research Products

    (15 results)

All 2004 2003 2002 2001 2000

All Journal Article (13 results) Book (1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Identification of Aberrantly Methylated Genes in Association with Adult T-Cell Leukemia.2004

    • Author(s)
      Yasunaga J-I.
    • Journal Title

      Cancer Res 64

      Pages: 6002-6009

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Aberrant expression of the MEL1S gene identified in association with hypomethylation in adult T-cell leukemia cells.2004

    • Author(s)
      Yoshida M.
    • Journal Title

      Blood 103

      Pages: 2753-2760

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Genetic and epigenetic inactivation of tax gene in adult T-cell leukemia cells.2004

    • Author(s)
      Takeda S.
    • Journal Title

      Int J Cancer 109

      Pages: 559-567

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Identification of aberrantly methylated genes in association with adult T-cell leukemia.2004

    • Author(s)
      Yasunaga J-I.
    • Journal Title

      Cancer Res 64

      Pages: 6002-6009

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro.2004

    • Author(s)
      Satou Y.
    • Journal Title

      Leukemia 18

      Pages: 1357-1363

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Human T-cell leukemia virus type I and adult T-cell leukemia.2003

    • Author(s)
      Matsuoka M.
    • Journal Title

      Oncogene 22

      Pages: 5131-5140

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Influence of cytokine and mannose binding protein gene polymorphisms on human T-cell leukemia virus type I (HTLV-I) provirus load in HTLV-I asymptomatic carriers.2003

    • Author(s)
      Nishimura M.
    • Journal Title

      Human Immunol 64

      Pages: 453-457

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Leukemogenesis of adult T-cell leukemia.2003

    • Author(s)
      Yasunaga J-I.
    • Journal Title

      Int J Hematol 78

      Pages: 312-320

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Mechanism of hypercalcemia in adult T-cell leukemia : Overexpression of RANK ligand on adult T-cell leukemia.2002

    • Author(s)
      Nosaka K.
    • Journal Title

      Blood 99

      Pages: 634-640

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Mechanism of hypercalcemia in adult T-cell leukemia : Overexpression of RANK ligand on adult T-cell leukemia.2002

    • Author(s)
      Nosaka, K.
    • Journal Title

      Blood 99

      Pages: 634-640

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Impaired production of naive T-lymphocytes in human T-cell leukemia virus type I infected individuals : its implications in the immunodeficient state.2001

    • Author(s)
      Yasunaga J-I.
    • Journal Title

      Blood 97

      Pages: 3177-3183

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Increasing Methylation of the CDKN2A Gene is Associated with the Progression of Adult T-Cell Leukemia.2000

    • Author(s)
      Nosaka K.
    • Journal Title

      Cancer Res 60

      Pages: 1043-1048

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Increasing Methylation of the CDKN2A Gene is Associated with the Progression of Adult T-Cell Leukemia-2000

    • Author(s)
      Nosaka K.
    • Journal Title

      Cancer Res. 60

      Pages: 1043-1048

    • Description
      「研究成果報告書概要(欧文)」より
  • [Book] Adult T-cell leukemia.(edited by Henderson ES, Lister TA, Greaves MF.)2002

    • Author(s)
      Matsuoka M.
    • Total Pages
      705-712
    • Publisher
      In Luekemia, 7th edition
    • Description
      「研究成果報告書概要(和文)」より
  • [Patent(Industrial Property Rights)] 抗Fas抗体HFE7Aおよびこれに関連する抗体による成人T細胞白血病の治療薬に関する発明2002

    • Inventor(s)
      松岡 雅雄, 米原 伸, 大隅 潤
    • Industrial Property Rights Holder
      三共株式会社
    • Industrial Property Number
      特願2002-142569
    • Filing Date
      2002-05-17
    • Description
      「研究成果報告書概要(和文)」より

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Published: 2008-05-27  

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