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Molecular diagnosis and theray of infantile acute leukemia carrying 11q23 translocations

Research Project

Project/Area Number 09670859
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionInstitute of Applied Biochemistry

Principal Investigator

AKAO Yukihiro  Institute of Appleed Bilchemistry, Chief Researcher, 研究部長 (00222505)

Co-Investigator(Kenkyū-buntansha) KUSAKABE Moriaki  RIKEN, Devision of Experrimental Animal Research, Chief Researcher, 室長 (60153277)
KOUMURA Sadaaki  Institute of Appleed Bilchemistry, Chief Researcher, 研究部長 (80211233)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1998: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1997: ¥2,500,000 (Direct Cost: ¥2,500,000)
KeywordsLeukemia / imfantile leukemia / chromosome translocation / 11q23 / MLLgene / antisense DNA / t(11;19) translocation / PCR / 染色体11番q23 / アンチセンスオリゴヌクレオチド / アポトーシス / ヒ素 / キメラ蛋白
Research Abstract

Chromosome band 11q23 is a common breakpoint of chromosome translocations in a variety of leukemias and lymphomas such as infantile leukemias and secondary leukemias associated with epipodophyllotoxin treatment. Generally, the leukemias carrying 1lq23 translocations have poor prognosis. Two groups cloned MLL which is involved in t(4 ; 11)(q21 ; q23) and t(11 ; 19)(q23 ; pl3). We also cloned the breakpoint of t(11 ; 19)(q23 ; pl3) translocations observed in KOCL33 and KOCL44 cell lines originated from infantile acute leukemias and found that the MLL-LTG19/ENL is formed by the t(11 ; 19) translocation. Further, it was found that MLL is involved in t(11 ; 17) and t(11 ; 22) translocations, and came to the conclusion that MLL is responsible for the major 11q23 translocations. A sequencing study demonstrated that MLL is related to the Drosophila trithorax gene encoding a protein containing two DNA-binding motifs as a transcriptional factor. The molecular mechanism of the leukemogenesis in 1lq23 translocations involving MLL is explained by the fact that the chimeric proteins from MLL-partner genes are produced in a nonregulated manner, resulting in the dysfunction of MLL protein, which could be the cause of leukemogenesis.
To clarify the role of MLL-LTG19 protein in leukemogenesis, we synthesized the antisense oligodeoxyribonucleotide (ODN) against the fused region of MLL-LTG19 chimeric transcript and treated KOCL33 cells having t(11 ; 19) with the antisense ODN. The antisense ODN inhibited cell growth and induced apoptosis in KOCL33 cells, but not in Daudi cells, which have no t(11 ; 19). The levels of MLL-LTG19 mRNA and MLL-LTG19 protein in KOCL33 cells treated with antisense ODN were shown to decrease with time by RT-PCR and Western blot analysis. These results suggest that the MLL-LTG19 fusion protein contributes to cell proliferation and malignant transformation in infantile acute leukemia cells having t(11 ; 19).

Report

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

    (6 results)

All Other

All Publications (6 results)

  • [Publications] Akao Y., Mizoguchi H., Ohishi N., Yagi K.: "Arsenic induces apoptosis in B-cell leukemic cell lines in vitro : activation of caspases and down-regulation of Bcl-2 protein"British Journal of Haematology. 102. 1055-1060 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Akao Y., Mizoguchi H., Ohishi N., Yagi K.: "Antisense oligodeoxyribonucleotide against the MILL-LTG19 chimeric transcript inhibits cell grownth and induces apoptosis in cells of an infantile leukemia cell line carrying the t(11 ; 19) translocation"Cancer Research. 58. 3773-3776 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Akao Y., Mizoguchi H., Ohishi H., Ohishi N., Yagi K.: "Arsenic induces apoptosis in B-cell leukemic cell lines in vitro: activation of caspases and down-regulation of Bcl-2 protein"Britishi Journal of Haematology. 102. 1055-1060 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Akao Y., Mizoguchi H., Ohishi H., Ohishi N., Yagi K.: "Antisense oligodeoxyribonucleotide against the MLL-LTG19 chimeric transcript inhibits cell growth and intuces apoptosis in cells of an infanitile leukemia cell line carrying the t(11;19) translocation"Cancer Research. 58. 3773-3776 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] AKao Y., Mizoguchi H., Ohishi N., Yagi K.: "Arsenic induces apoptosis in B-cell leukemic cell lines in vitro: activation of caspases and down-regulation of Bcl-2 protein" British Journal of Haematology. 102. 1055-1060 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] AKao Y., Mizoguchi H., Ohishi N., Yagi K.: "Antisense oligodeoxyribonucleotide against the MLL-LTG19 chimeric transcript inhibits cell growth and induces apoptosis in cells of an infantile leukemia cell line carrying the t(11;19) translocation" Cancer Research. 58. 3773-3776 (1998)

    • Related Report
      1998 Annual Research Report

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

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