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Molecular Analysis of Transformation into Blast Crisis in Chronic Myelogenous Leukemia

Research Project

Project/Area Number 02671117
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Hematology
Research InstitutionHokkaido University

Principal Investigator

OKABE Mihiro  Hokkaido University, School of Medicine, Medical Hospital, Instructor, 医学部附属病院, 助手 (40113534)

Project Period (FY) 1990 – 1992
Project Status Completed (Fiscal Year 1992)
Budget Amount *help
¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1992: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1991: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1990: ¥800,000 (Direct Cost: ¥800,000)
Keywordschronic myelogenous leukemia / blast crisis / bcr-abl gene / ras gene / p53 anti-oncogene / herbimycin A / antisense oligonucleotides / antisense oligonucleotides / abl tyrosine kinase / 慢性骨髄性白血病(CML) / p53遺伝子 / ablチロシンキナ-ゼ / transforming遺伝子 / Herbimycin A / bcrーabl遺伝子 / fms遺伝子 / 癌抑制遺伝子
Research Abstract

Molecular events associated with the transformation into blast crisis phase in Ph^1-positive CML were analyzed. The Southern blot and RT-PCR analyses revealed that no obvious difference between both chronic and crisis phases was observed regarding the breakpoints on bcr gene and the fusional mode of bcr-abl gene. However, blast crisis cells showed the enhanced expression of bcr-abl mRNA, when compared with those of chronic phase cells. By the DNA transfection and PCR analyses, the point-mutational activation of ras oncogene was rarely identified. On the other hand, myeloid crisis cells frequently showed alterations of the p53 anti-oncogene and of its expression. The present study suggested one possibility that a selective and progressive process of Ph^1 clone with high expression of the bcr-abl gene may be involved with the transformation into the myeloid crisis from the chronic phase, and further this progression may be accelerated by the loss of function of anti-oncogene, p53 gene due to the disturbance of a check point on Gl*S entrance.
Consequently, the investigation of a new strategy of bcr/abl oncoprotein-targeted therapeutics was carried out. Antisense oligodeoxynucleotides complementary to bcr-abl mRNA showed no desired antitumor activity, thus indicating that devices of chemical modification and delivery system may bring the future therapeutic application. On the contrary, herbimycin A, an inhibitor of PTK, showed the bcr/abl oncoprotein-targeted antitumor activity on Ph^1-positive leukemia cells and bcr/abl oncogene-transfected cells. These findings were presented in mamuscripts and review articles of English journals.

Report

(4 results)
  • 1992 Annual Research Report   Final Research Report Summary
  • 1991 Annual Research Report
  • 1990 Annual Research Report
  • Research Products

    (28 results)

All Other

All Publications (28 results)

  • [Publications] OKABE Mihiro: "Review article:New insight into oncoprotein-targeted anti-tumor effect" Leukemia and Lymphoma(in press). (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] OKABE Mihiro: "BCR/ABL oncoprotein-targeted antitumor activity of antisense oligodeoxynucleotides complementary to bcr/abl mRNA and herbimycine A,an antagonist of protein tyrosine kinase." Leukemia and Lymphoma(in press). (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] OKABE Mihiro: "Effect of herbimycin A, an antagonist of tyrosine kinase,on bcr/abl oncoprotein-associated cell proliferations." Blood. 80. 1330-1338 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] OKABE Mihiro: "Review article:Inhibitory anti-tumor effects of interleukin-4 on Philadelphia chromosom-positive acute lymphocytic leukemia and other hematopoietic malignancies." Leukemia and Lymphoma. 8. 57-63 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] OKABE Mihiro: "Inhibitory effect of interleukin-4 on the in vitro growth of ph^1-positive actute-lymphoblastic leukemia cells." Blood. 78. 1574-1580 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] OKABE Mihiro: "Blast crisis accompanied with occurrence・of the point-mutational activation of N-ras proto-oncogene and the chromosomal abnormality inv(3q)in chronic myelogenous leukemia presenting thrombocytosis." Leukemia. 4. 381-382 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Mihiro Okabe: "Review article:New insight into oncoprotein-targeted antitumor effect." Leukemia and Lymphoma. (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Mihiro Okabe: "BCR-ABL oncoprotein-targeted antitumor activity of antisense oligodeoxynucleotides complementary to bcr/abl mRNA and herbimycine A, an antagonist of protein tyrosine kinase:Inhibitory effects on in vitro growth of Ph^1-positive leukemia cells and bcr/abl oncoprotein-associated trans-formed cells." Luekemia and Lymphoma. (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Mihiro Okabe: "Effect of herbimycine A, and antagonist of tyrosine kinase, on bcr/abl oncoprotein-associated cell proliferations:Abrogative effect on the transformation of murine hematopoietic cells by transfection of a retroviral vector expressing oncoprotein P210 bcr/abl and preferential inhibition on Ph^1-positive leukemia cell growth." Blood. 80. 1330-1338 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Mihiro Okabe: "Review article:Inhibitory antitumor effects of interleukin-4 on Philadelphia chromosom-positive acute lymphocytic leukemia and other hematopoietic malignancies." Luekemia and Lymphoma. 8. 57-63 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Mihiro Okabe: "Inhibitory effect of interleukin-4 on the in vitro growth of Ph^1-positive acute lymphoblastic leukemia cells." Blood. 78. 1574-1580 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Mihiro Okabe: "Blast crisis accompanied with occurrence of the point-mutational activation of N-ras proto-oncogene and the chromosomal abnormality inv (3q) in chronic myelogenous leukemia presenting thrombocytosis." Leukemia. 4. 381-382 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Okabe Mihiro: "Review article:New aspects of oncoprotein‐targeted antitumor effect." Leukemia and Lymphoma. (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] Okabe Mihiro: "BCR/ABL oncoprotein‐targeted antitumor activity of antisense oligodeoxynucleotides complementary to bcr/abl mRNA and herbimycine A,an antagonist of protein tyrosine kinase." Leukemia and Lymphoma. (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] 黒沢 光俊: "アンチセンス法による自家骨髄のパージングの可能性" ディオ メディカ. (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] 岡部 實裕: "慢性骨髄性白血病における急性転化の分子遺伝学的研究" 北海道医学会誌. (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] Okabe Mihiro: "Effect of herbimycine A,an antagonist of tyrosine kinase,on bcr/abl oncoprotein‐associated cell proliferations." Blood. 80. 1330-1338 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Okabe Mihiro: "Review article:Inhibitory anti‐tumor effects of interleukin‐4 on Philadelphia chromosome‐positive acute lymphocytic leukemia and other hematopoietic malignancies." Luekemia and Lymphoma. 8. 57-63 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 森岡 正信,岡部 實裕: "Ph^1陽性ALLの臨床病態と予後" 臨床血液. 32. 354-360 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] 国枝 保幸,岡部 實裕: "CML,ALLにおけるbcr再構成とbcr/abl遺伝子の発現" 臨床血液. 32. 623-628 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] 岡部 實裕 他: "Ph^1陽性白血病の分子生物学:bcr/abl遺伝子研究の新展開と臨床病態解析への応用" 医学のあゆみ. 158. 309-313 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Mihiro OKABE et al: "Inhibitory effect of interleukinー4 on the in vitro growth of Ph^1ーpositive acute lymphoblastic leukemia cells" Blood. 78. 1574-1580 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Mihiro OKABE: "Blast crisis accompanied with occurrence of the pointーmutational activation of Nーras protoーoncogene and the chromosomal abnormality inv(3q)in chronic myelogenous leukemia presenting thromlocytosis" Leukemia. 4. 381-382 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Toshio Higa: "In vitro differentiation to monocytoid lincage of aniw ph^1ーpositive ALL cell line presenting the breakpoint on berー2" Leukemia.

    • Related Report
      1990 Annual Research Report
  • [Publications] Mihiro OKABE: "Establishment and characterization of a CML crisisーderived cell line(MC3)contnining alteration of p53 gene" submitted.

    • Related Report
      1990 Annual Research Report
  • [Publications] Mihiro OKABE: "Abnormal expressions of p53 gene in blastic crisis of chronic myelogenous leukemia" Submitted.

    • Related Report
      1990 Annual Research Report
  • [Publications] 国枝 保幸: "Ph^1陽性白血病におけるbcrーabl遺伝子再構成と発現" 日本臨床血液学会誌. (1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] 岡部 實裕: "cーabl遺伝子とPh^1陽性白血病におけるbcrーabl融合遺伝子" 日本臨床 特集:癌遺伝子.癌抑制遺伝子. 48. 1697-1705 (1990)

    • Related Report
      1990 Annual Research Report

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Published: 1990-04-01   Modified: 2016-04-21  

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