THE RELATION OF VARIANT MLL GENE TO CELL DEATH AND UNRESPONSIVENESS TO CHEMOTHERAPY IN INFANTILE LEUKEKEMIA WITH 11q23 TRANSLOCATION
| Project/Area Number |
12670221
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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 |
Experimental pathology
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| Research Institution | INSTITUTE OF APPLIED BIOCHEMISTRY |
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Principal Investigator |
AKAO Yukihiro INSTITUTE OF APPLIED BIOPCHEMISTRY, CHIEF, 研究部長 (00222505)
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| Co-Investigator(Kenkyū-buntansha) |
KUSAKABE Moriaki EXPERIMENTAL ANIMAL DIVISION OF RIKEN CHIEF, 実験動物室長 (60153277)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2000: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | INFANTILELEUKEMIA / CHROMOSOMAL TRANSLOCATION / MLLGENE / APOPTOSIS / DRUG RESISTENCE / CHIMERIC PROTEIN / 造血器腫瘍 / 11q23 / MILL遺伝子 / MLL / 細胞増殖抑制 / 亜ヒ酸 |
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| Research Abstract |
Chromosome translocations including 11q23 have been shown to be associated with a variety of hematopoietic malignancies, including de novo infant and adult acute myeloid, lymphoid, or biphenotypic leukemia, and secondary acute myeloid leukemias especially induced by topoisomerase II inhibitory drugs. Especially, the majority of infant acute leukemias show abnormalities of chromosome band 1 1q23.The breakpoints of t(4 ; 11)(q21 ; q23) and t(11 ; 19)(q23 ; p13) in infantile acute leukemia were cloned and a novel gene at 11q23 called MLL was identified. MLL shows a strong homology to the Drosophila trithorax, which is involved in body segmentation. MLL has two types of DNA binding motifs, AT hooks and zinc fingers, and acts as a transcriptional factor. Chromosome translocation involving MLL results in the production of fusion mRNA consisting of a part of the MLL gene and a part of another gene on the partner chromosome. Chromosomal analysis of acute monocytic leukemia cells in an infantil
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e female revealed a t(6 ; 11)(q27 ; q23) translocation. Southern blot analysis with a cDNA probe of the MLL gene on chromosome 11q23 indicated that the breakpoint was in a 8.3-kb BamHI fragment that carried exons 5-11 of MLL gene. Northern blot analysis showed a faint band corresponding to MLL chimeric transcript. Structual analysis of a genomic clone carrying the rearranged MLL gene, which originates from der(11) chromosome, demonstrated the breakpoint to be localized between exons 6 and 7 of the MLL gene and to lie in the Alu sequence of this region. The partner gene fusing to 3 of MLL was shown to be AF6 gene on chromosome 6q27 by in situ chromosome hybridization and nucleotide sequencing of chimeric MLL cDNA clones. However, it was shown that the exon 5 of MLL was fused to AF6 in a clone except major MLL exon 6/AF6 chimeric cDNA clones. These findings indicate that exon 6 of MLL is spliced out in the process of transcription in a variant MLL/AF6.In clinical course, the amount of variant MLL/AF6 evaluated by RT-PCR was associated with the unresponsiveness to chemotherapy. Less
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Report
(3 results)
Research Products
(9 results)
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[Publications] Kitamura,K.,Minami,Y.,Yamamoto,K.,Akao,Y.,Kiyoi,H.,Naoe,T.: "Involvement of CD95-independent caspase 8 activation in arsenic trioxide-induced apoptosis."Leukemia. 14. 1743-1750 (2000)
