| Project/Area Number |
04557133
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Hematology
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| Research Institution | University of Tokyo |
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Principal Investigator |
HIRAI Hisamaru University of Tokyo, Department of Internal Medicine, Associate Professor, 医学部(病), 講師 (90181130)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Tomoyuki University of Tokyo, Department of Internal Medicine, Assistant Professor, 医学部(病), 助手 (50227154)
HANAZONO Yutaka University of Tokyo, Department of Internal Medicine, Assistant Professor, 医学部(病), 助手 (70251246)
MITANI Kinuko University of Tokyo, Department of Internal Medicine, Assistant Professor, 医学部(病), 助手 (50251244)
杉本 耕一 東京大学, 医学部(病), 医員
千葉 滋 東京大学, 医学部(病), 助手
豊島 秀男 東京大学, 医学部(病), 助手 (20197966)
間野 博行 東京大学, 医学部(病), 助手 (90240704)
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| Project Period (FY) |
1992 – 1994
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| Project Status |
Completed (Fiscal Year 1994)
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| Budget Amount *help |
¥15,200,000 (Direct Cost: ¥15,200,000)
Fiscal Year 1994: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1993: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1992: ¥6,200,000 (Direct Cost: ¥6,200,000)
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| Keywords | chromosomal translocation / AML1 / EVI-1 / chimeric protein / transcription factor / suppressor oncogene / p16 gene / ALL / EVi-1 / 癌抑制遺伝子 / 転座型白血病 / 慢性骨髄性白血病 / 急性転化 / t(3;21)転座 / AML1 / EVI-1キメラ遺伝子 / 転写因子 / 急性前骨髄球性白血病 / PML / RARのキメラ遺伝子 / t(15;17)転座 / RT-PCR法 / 複合転座 |
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| Research Abstract |
The t (3 ; 21) (q26 ; q22)translocation, which is one of consistent chromosomal abnormalities found in blastic crisis of chronic myelocytic leukemia(CML) , is thought to play an important role in leukemic progression of CML to an acute blastic crisis phase. The AML1 gene, which is located at the translocation breakpoint of the t (8 ; 21) (q22 ; q22) translocation found in acute myelocytic leukemia, was also rearranged by the t (3 ; 21) (q26 ; q22) translocation. Screening of a cDNA library of the t (3 ; 21) -carrying leukemic cell line cells (SKH1) resulted in the isolation of AML1/EVI-1 chimeric cDNAs. SKH1 cells expressed the 180 kD AML1/EVI-1 fusion protein containing an amino-terminal half of AML1 including a runt homology domain which is fused to the entire of zinc finger EVI-1 protein. These findings strogly suggest that the t (3 ; 21) translocation results in the fromation of a new class of a chimeric transcription factor which could contribute to leukemic progression of CML thr
… More
ough interference with cell growth and differentiation. Biochemical analyzes revealed that AML1/EVI-1 itself does not alter the transactivation level through PEBP2 sites but dominantly suppresses the transactivation by intact AML1, which is assumed to be a stimulator of myeloid cell differentiation. The DNA-binding competition is a putative mechanism of such dominant negative effects of AML1/EVI-1 because it binds to PEBP2 sites in the higher affinity than AML1.
Furthermore, AML1/EVI-1 stimulated the c-fos promoter transactivation and raised the AP-1 activity. Experiments, using deletion mutants of AML1/EVI-1, showed that these two functions are mutually independent because the dominant negative effects upon intact AML1 and the stimulation of AP-1 activity are dependent on the runt domain and the zinc finger domain near the C-terminus, respectively. Furthermore we showed that AML1/EVI-1 blocks granulocytic differentiation, otherwise induced by G-CSF,of 32Dc13 myeloid cells. It was also suggested that both AML1-derived and EVI-1-derived portions of the fusion protein play crucial roles for such differentiation block. We conclude that the leukemic cell transformation in t (3 ; 21) leukemias is probably caused by those dual functions of AML1/EVI-1 chimeric protein. Less
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