Molecular diagnosis and theray of infantile acute leukemia carrying 11q23 translocations
| Project/Area Number |
09670859
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Institute of Applied Biochemistry |
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Principal Investigator |
AKAO Yukihiro Institute of Appleed Bilchemistry, Chief Researcher, 研究部長 (00222505)
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| 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)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| 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)
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| Keywords | Leukemia / 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 |
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| 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).
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Report
(3 results)
Research Products
(6 results)
