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Identification and analysis associated with the onset and progression of adult T-cell leukemia

Research Project

Project/Area Number 09671125
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionKumamoto University School of Medicine

Principal Investigator

MATSUOKA Masao  Department of Internal Medicine, Kumamoto University School of Medicine, Associate Professor, 医学部・附属病院, 講師 (10244138)

Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1998: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1997: ¥2,300,000 (Direct Cost: ¥2,300,000)
KeywordsAdult T-cell leukemia / HTLV-I / p16 / apoptosis / Fas / methylation / multi-step tumorigenesis / leukemogenesis / 成人T細胞 / ヒトリンパ向性ウイルスI型 / 癌遺伝子 / 癌抑制遺伝子
Research Abstract

Adult T-cell leukemia (ATL) is an aggressive neoplasm of helper T-lymphocytes, which is etiologically associated with human T-cell leukemia virus type I (HTLV-I). Siince its long latent period from infection of HTLV-I to onset of ATL, multti-step mechanism of leukemogenesis is considered in ATL.We are trying to identify the genes responsible for the onset and the progression of ATL.Although leukemic cells in most ATL cases expressed Fas antigen, we found Fas-negative cases. Neutrophil from this patient had Fas antigen on the surface, showing that Fas-negative phenotype is specific to leukemie cells. Sequences of RT-PCR products revealed that skipping of exon 4, and small deletion (5bp) caused premature termination of Fas protein synthesis, resulting in Fas negative phenotype. This Fas negative ATL cells were resistant to doxorubicin -induced apoptosis in vitro. Fas negative phenotype is considered to be associated with drug resistance.
Methylation of the p16^<INK4A> gene has been recogn … More ized as another mechanism, in addition to somatic DNA changes such as deletion or mutation, which can inactivate the pl6^<INK4A> gene in various malignancies including melanoma, bladder cancer and malignant lymphoma. We analyzed the methylation of the p16^<INK4A> gene in patients with different subtypes of adult T-cell leukemia (ATL). Using Southern blot analysis and methylation-specific PCR (MSPCR), we detected methylation of the p16^<INK4A> gene was more frequently in acute ATL (49%) or lymphoma-type ATL (73%) than in lowgrade malignant stage, chronic (17%) and smoldering types (17%). In contrast, no methylation of the pl6^<INK4A> gene was found in asymptomatic HTLV-I carriers and uninfected control, and methylation of the p15 gene, which encode another inhibitor of CDK4 and 6, could not be found in any ATL samples : methylation of the p16^<INK4A> gene is highly specific for ATL.Deletion of the the p16^<INK4A> gene was found in another 20% of acute ATL patients by Southern blot analysis, and therefore, abnormalities of the p16^<INK4A> gene in acute ATL total to 69%. Furthermore, direct sequencing of the pl6^<INK4A> gene after sodium bisulfite treatment of genomic DNA revealed that the methylation of CpG sites occurred in most (23 out of 29) of ATL cases including chronic or smoldering ATL, even in the cases which methylation could not be detected by MSPCR or the Southern blot method. Semi-quantitative PCR showed markedly decreased p16^<INK4A> mRNA levels in the samples having a methylated p16^<INK4A> gene. These findings show that a level of CpG methylation plays an important role in the progression of ATL by further decreasing the expression of p16. Less

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Etoh K, 他7名: "Persistent clonal proliferation of human T-lymphotropic virus type I-infected cells in vivo." Cancer Research. 57. 4862-4867 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Takemoto S, 他12名: "Proliferation of adult T-cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins." Proc. Natl. Acad. Sci. USA. 94. 13897-13902 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Matsuoka M, 他4名: "HTLV-1 provirus in the clinical subtypes of ATL." Leukemia. 11. s67-69 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Arai M, 他5名: "Expression of FAP-1(Fas associated phosphatase)and resistance to Fas-mediated apoptosis in T cell lines derived from human T cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis patients." AIDS Res Human Retroviruses. 14. 261-267 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tamiya S, 他3名: "Mutation of CD95(Fas/Apo-1)genes in adult T-cell leukemia cells." Blood. 91. 3935-3942 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Inoue M, 他4名: "Characterization of mRNA expression of IkappaB alpha and NF-kappaB subfamilies in primary adult T-cell leukemia cells." Jpn. J. of Cancer Res.89. 53-59 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Etoh K-I, 他8名: "Rapid quantification of HTLV-I provirus load:detection of monoclonal proliferation of HTLV-I-infected cells among blood donors." Int. J, Cancer. (in press). (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 松岡 雅雄、他: "成人T細胞白血病リンパ腫. 悪性リンパ腫治療マニュアル" 南江堂, 213 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Etoh K,Matsuoka M,et al.: "Persistent clonal proliferation of human T-lymphotropic virus type I-infected cells in vivo" Cancer Research. 57. 4862-4867 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Takemoto S,Matsuoka M,et al.: "Proliferation of adult T-cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins." Proc.Natl.Acad.Sci.USA. 94. 13897-13902 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Matsuoka M,Takatsuki K,et al.: "HTLV-1 provirus in the clinical subtypes of ATL." Leukemia. 11. s67-69 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Arai M,Matsuoka M,et al.: "Expression of FAP-1 (FASassociated phosphatase) and resistance to Fas-mediated apoptosis in T cell lines derived from human T cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis patients." AIDS Res.Human Retro. 14. 261-267 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tamiya S,Matsuoka M,et al: "Mutation of CD95 (Fas/Apo-1) genes in adult T-cell leukemia cells." Blood. 91. 3935-3942 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Inoue M,Matsuoka M,et al: "Characterization of mRNA expression of IkappaB alpha and NF-kappaB subfamilies in primary adult T-cell leukemia cells." Jpn.J.of Cancer Res.89. 53-59 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Etoh K-I,Matsuoka M,et al: "Rapid quantification of HTLV-I provirus load : detection of monoclonal proliferation of HTLV-I-infected cells among blood donors." Int.J.Cancer. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Arai M、他5名: "Expression of FAP-1(Fas associated phosphatase)and resistance to Fas-mediated apoptosis in T cell lines derived from human T cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis patiens." AIDS Res Human Retroviruses. 14. 261-267 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tamiya S、他3名: "Mutation of CD95(Fas/Apo-1)genes in adult T-cell leukemia cells." Blood. 91. 3935-3942 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Inoue M、他4名: "Characterization of mRNA expression of IkappaB alpha and NF-kappaB subfamilies in primary adult T-cell leukemia cells." Jpn.J.Of Cancer Res.89. 53-59 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Oshima K、他8名: "Random integration of HTLV-I provirus;increasing chromosomal instability." Cancer Letters. 132. 203-212 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Etoh K-I、他8名: "Rapid quantification of HTLV-I provirus load:detection of monoclonal proliferation of HTLV-I-infected cells among blood donors." Int.J.Cancer. in press. (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tekemoto, S., et al.: "Proliferation of asult T cell leukemia/lymphoma cells is assiciated with the constitutive activation of JAK/STAT proteins." Proc. Natl. Acad. Sci. USA. 94. 13897-13902 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Etoh, K-I., et al.: "Persistent clonal proliferation of human T-lymphotropic virus type I-infected cells in vivo." Cancer Res. 57. 4862-2867 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Arai, M., et al.: "Expression of FAP-1 (Fas associated phosphatase) and resistance to Fas-mediated apoptosis in T cell lines derived from human T cell leukemia virus type 1-ssociated myelopathy/tropical spastic paraparesis patients." AIDS Res Human Retroviruses. 14. 261-267 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tamiya, S., et al.: "Mutation of CD95 (Fas/Apo-1) genes in adult t-cell leukemia cells." Blood. (in press).

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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