| Project/Area Number |
10470177
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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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 | Yamanashi Medical University |
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Principal Investigator |
NAKAZAWA Shinpei Yamanashi Medical University Professor, 医学部, 教授 (90090034)
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| Co-Investigator(Kenkyū-buntansha) |
GOI Kumiko Yamanashi Medical University Research Associate, 医学部, 助手 (70324192)
INUKAI Takeshi Yamanashi Medical University Research Associate, 医学部, 助手 (30293450)
SUGITA Kanji Yamanashi Medical University Assistant-Professor, 医学部, 講師 (60138055)
手塚 徹 山梨医科大学, 医学部, 助手
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| Project Period (FY) |
1998 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 2000: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1999: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1998: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Keywords | Leukemia / Apoptosis / Chemotherapy / Translaocation / Transcriptin factor / Cytokine / 11q23転座型白血病 / 9;22転座型白血病 / 17;19転座型白血病 / 小児急性リンパ性白血病 / 化学療法 / ステロイド剤 / G-CSF / 多剤耐性 |
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| Research Abstract |
Inhibition of apoptosis plays an important role in leukemogenesis and chemo-resistance of childhood leukemias. In this study, to provide clue for better therapeutic outcome in childhood leukemias, we have tried to verify the mechanism of leukemogenesis and chemo-resistance particularly by shedding light on apoptosis.
1.We found out the expression of PPARγ, member of the steroid receptor family, in the leukemic cells. In the presence of ligand, leukemic cells underwent apoptosis through the downregulation of c-myc expression, suggesting that PPARγligand is one of the novel candidates for chemotherapeutic agents for leukemias.
2.We tested the expression of the cytokine receptors in leukemic cells and found out that both G-CSF receptor and TPO receptor are frequently expressed in the leukemic cells derived in stem cell level, such as Ph1 -positive and 11q23-related translocation-positive leukemias. In the presence of G-CSF or TPO, the proliferation of several leukemic cells was activated, s
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uggesting that these cytokines enhance the pro-apoptotic activities of chemotherapeutic reagents.
3.We have identified a SLUG transcription factor gene as a downstream target of antiapototic activity of the E2A-HLF fusion transcription factor derived form t (17 ; 19) in childhood leukemias. We analyzed the configuration of human SLUG gene in comparison with that of mouse gene and found out that the region about 1kb upstream of major start site of human SLUG gene shows an extremely high identity in the sequence to that of mouse gene. EMSA using this region as a probe indicated the specific binding of E2A-HLF, suggesting that E2A-HLF directly upregulates the SLUG gene expression through this region.
4.We analyzed the apoptosis induced by the serum-deprivation in 11q23-related translocation-positive leukemias and found out that 6 out of 9 cell lines established in our laboratory showed the resistance in apoptosis, suggesting that anti-apoptoic features play an important role in the disease progression in this type of leukemia. Less
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