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Search for the regulatory factor of apoptosis in adult T-cell leukemia (ATL) cells

Research Project

Project/Area Number 12670993
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionNagasaki University

Principal Investigator

MAEDA Takahiro  University Hospital, School of Medicine, Nagasaki University Assistant Professor, 医学部・附属病院, 助教授 (40284674)

Co-Investigator(Kenkyū-buntansha) KAMIHIRA Shimeru  University Hospital, School of Medicine, Nagasaki University, Professor, 医学部, 教授 (80108290)
MORIUCHI Ryuzou  Graduate School of Medicine Science, Nagasaki University Assistant Professor, 大学院・医学研究科, 助教授 (60210142)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2000: ¥2,500,000 (Direct Cost: ¥2,500,000)
KeywordsFas / adult T-cell leukemia / ATL / apoptosis / genetic mutation / trimer
Research Abstract

1. Anti-Fas monoclonal antibody (mAb) resistant adult T-cell leukemia (ATL) cell line, RS04
RS04 RS04 cells did not show apoptosis after treatment with IgM anti-Fas mAb. We found that the lactacystin, which was a specific inhibitor of the proteosome, activated the caspase 8 and induced apoptosis in RS04 cells, indicating that the apoptotic pathway in the cytoplasm in RS04 cells was intact. By sequencing analysis of Fas gene, we found the heterozygous missense mutation with the transition of A to G at exon 2, resulting in substitution of arginine for histidine. The three dimensional molecular modeling of the mutated Fas protein indicated the definitive conformational alteration around the amino acids 52 to 58. It was suggested that the trimerization of Fas molecules was interfered with the mutated Fas, resulting in the impairment of signal transduction of apoptosis by dominant negative mechanism.
2. Anti-Fas mAb resistantATL cell line, OMT
In OMT cells, we found the missense point mutation at nucleotide 1132 with the transition of T to C, resulting in the substitution of threonine for isoleucine. This mutation might cause the conformational alteration of death domain and fail to associate with the FADD molecule, which located at right downstream under the Fas molecule.
3. ATL cells which barely express membrane Fas
Because the Fas gene mutations were detected at the relatively high rate in Fas-resistant ATL cell lines, we investigated the primary ATL cells, which barely expressed membrane Fas and were resistant to IgM anti-Fas mAb. In four of seven cases of patients with ATL, we found Fas gene mutations, three point mutations and a 2 base pair deletion. It was indicated that the various mutations of Fas gene were one of the mechanisms of preventing the apoptosis in ATL cells.

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (33 results)

All Other

All Publications (33 results)

  • [Publications] Kemihira S.: "Clinical and oncological significance of aberrant Fas (APO-1/CD95) isoform expression in adult T-cell leukemia"Indian J. Clin. Biochem.. 15. 101-109 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kamihira S.: "Real-time polymerase chain reaction for quantification of HTLV-1 proviral load : application for analyzing aberrant integration of the proviral DNA in adult T-Cell leukemia"Int. J. Hematol.. 72. 79-84 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamada Y.: "Lactacystin activates FLICE (caspase 8) protease and induces apoptosis in Fas-resistant adult T-cell leukemia cell lines"Eur. J. Haematol.. 64. 315-322 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Maeda T.: "Successful treatment with a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8,rituximab) for a patient with relapsed mantle cell lymphoma who developed a human anti-chimeric antibody"Int. J. Hematol.. 74. 70-75 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Isomoto H.: "Adult T-cell leukemia with unusual esophageal lesion"Gastrointest. Endosc. 53. 673-676 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Isomoto H.: "Clinical and endoscopic features of adult T-cell leukemia/lymphoma with duodenal involvement report of three cases with a review of literature"J. Clin. Gastroenterol. 38. 241-246 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Maeda T.: "Apoptosis part II : the role of mutated Fas genes in tumorigenesis"Adv. Clin. Chem.. 36. 109-137 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hayashibara T.: "Vascular endothelial growth factor and cellular chemotaxis : a possible autocrine pathway in adult"Clin. Cancer Res.. 7. 2719-2726 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Okazaki S.: "HTLV-1 proviruses encoding non-functional TAX in adult T-cell leukemia"Virus Genes. 23. 123-135 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Isomoto H.: "Clinical and endoscopic features of adult T-cell leukemia/lymphoma with duodenal involvement"J. Clin. Gastroenterol.. 33. 241-246 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Isomoto H.: "Jejunal perforation in a patient with adult T-cell leukemia"Leukemia and Lymphoma. 42. 1423-1427 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kemihira S.: "Clinical and oncological significance of aberrant Fas (APO-1/CD95) isoform expression in adult T-cell leukemia"Indian J. Clin. Biochem.. 15. 101-109 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kamihira S.: "Real-time polymcrase chain reaction for quantification of HTLV-1 proviral load: application for analyzing aberrant integration of the proviral DNA in adult T-Cell leukemia"Int. J. Hematol.. 72. 79-84 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamada Y.: "Lactacyfitin activates FLICE(caspaee 8)protease and induces apoptosis in Fas-resistant adult T-cell leukemia cell lines"Eur. J. Hematol.. 64. 315-322 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Maeda T.: "Successful treatment with a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8,rituximab)for a patient with relapsed mantle cell lymphoma who developed a human anti-chimeric antibody"Int. J. Hematol.. 74. 70-75 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Isomoto H.: "Adult T-cell leukemia with unusual esophageal lesion"Gaatrointest. Endosc.. 53. 673-676 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Isomoto H.: "Clinical and endoscopic features of adult T-cell leukemia/lymphoma with duodenal involvement report of three cases with a review of literature"J. Clin. Gastroenterol.. 33. 241-246 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Maeda T.: "Apoptosis, part II :the role of mutated Fas genes in tumorigenesis"Adv. Clin. Chem.. 36. 109-137 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hayashibara T.: "Vascular endothelial growth factor and cellular chemotaxis: a possible autocrine pathway in adult T-cell leukemia cell invasion"Clin. Cancer Res.. 7. 2719-2726 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Okazaki S.: "HTLV-1 proviruses encoding non-functional TAX in adult T-cell leukemia"Virus Genes. 23. 123-135 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Isomoto H.: "Clinical and endoscopic features of adult T-cell leukemia/lymphoma with duodenal involvement"J. Clin. Gastroenterol.. 33. 241-246 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Isomoto H.: "Jejunal perforation in a patient with adult T-cell leukemia"Leukemia and Lymphoma. 42. 1423-1427 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Maeda T.: "Apoptosis part II : role of mutated Fas genes in tumorigenesis."Adv.Chin.Chem.. 36. 109-137 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hayashibara T.: "Vascular endothelial growth factor and cellular chemotaxis : a possible autocrine pathway in adult T-cell leukemia cell invasion."Clin.Cancer Res.. 7. 2719-2726 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Okazaki S.: "HTLV-1 proviruses encoding non-functional TAX in adult T-cell leukemia."Virus Genes. 23. 123-135 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Isomoto H.: "Clinical and endoscopic features of adult T-cell leukemia/lymphoma with duodenal involvement."J.Clin.Gastroenterol.. 33. 241-246 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Isomoto H.: "Jejunal perforation in a patient with adult T-cell leukemia."Leukemia and Lymphoma. 42. 1423-1427 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Maeda T.: "Success treatment with a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8,rltuximab) for a patient with relapsed mantle cell lymphoma who developed a human anti-chimeric antibody."Int.J.Hematol.. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Isomoto H.: "Adult T-cell leukemia with unusual esophageal lesion."Gastrointest.Endosc.. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Isomoto H.: "Clinical and endoscopic features of adult T-cell leukemia/lymphoma with duodenal involvement report of three cases with a review of literature."J.Clin.Gastroenterol.. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Kamihira S.: "Clinical and oncological significance of aberrant Fas (APO-1/CD95) isoform expression in adult T-cell leukemia."Indian J.Clin.Biochem.. 15. 101-109 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kamihira S.: "Real-time polymerase chain reaction or quantification of HTLV-1 proviral load : application for analyzing aberrant integration of the proviral DNA in adult T-cell leukemia."Int.J.Hematol.. 72. 79-84 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yamada Y.: "Lactacystin activaes FLICE (caspase 8) protease and induces apoptosis in Fas-resistant adult T-cell leukemia cell lines."Eur.J.Haematol.. 64. 315-322 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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