| Project/Area Number |
16591017
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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 | University of Yamanashi |
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Principal Investigator |
INUKAI Takeshi University of Yamanashi, Department of Research Interdisciplinary Graduate School of Medicine and Engineering, Research Associate, 大学院・医学工学総合研究部, 助手 (30293450)
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| Co-Investigator(Kenkyū-buntansha) |
GOI Kumiko University of Yamanashi, Department of Research Interdisciplinary Graduate School of Medicine and Engineering, Research Associate, 大学院・医学工学総合研究部, 助手 (70324192)
AKAHANE Koshi University of Yamanashi, University of Yamanashi Hospital, Medical Staff, 医学部附属病院, 医員 (90377531)
KUDODA Itaru University of Yamanashi, University of Yamanashi Hospital, Medical Staff, 医学部附属病院, 医員 (30402051)
廣瀬 衣子 山梨大学, 医学部附属病院, 医員
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2004: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | leukemia / apoptosis / cytotoxic ligands / endoplasmic reticulum-stress / GVL effect / 11q23 rearranged leukemia / T-cell leukemia / Ph1-positive leukemia / 同種造血幹細胞移植 / Fas / TRAIL |
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| Research Abstract |
First, we analyzed anti-leukemic activity of TRAIL against 11q23-rearranged acute lymphoblastic leukemias (ALL), which are relatively resistant to allogeneic stem cell transplantation (allo-SCT). Eight of 9 ALL cell lines with 11q23 rearrangement were highly resistant to TRAIL due to low cell surface expression of DR4 and DR5, death receptors for TRAIL. Moreover, most of the clinical samples from 11q23-rearranged infant ALL patients were highly resistant to anti-leukemic activity of TRAIL. The expression levels of DR4 and DR5 were relatively low compared with samples from Ph1-positive ALL patients, which were frequently sensitive to TRAIL. These observations strongly suggest that resistance to TRAIL is one of mechanisms for relatively poor outcome of allo-SCT in the patients with 11q23-rearranged infant ALL.
Next, we analyzed anti-leukemic activity of TRAIL and FasL against T-cell ALL. Six of 7 T-ALL cell lines were resistant to TRAIL but highly sensitive to FasL. Most of T-ALL cell lin
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es were negative for DR4 and DR5 expressions in both flow cytometric and real-time RT-PCR analysis but were positive for Fas expression. Consistently, all of clinical samples from the patients with T-ALL were negative for DR4 and DR5 but positive for Fas. Considering that outcome of allo-SCT for T-ALL was reported to be almost equivalent for that for B-precursor ALL, these data suggest that FasL rather that TRAIL plays an essential role in the GVL effect for T-ALL.
Finally, we analyzed the effects of endoplasmic reticulum (ER)-stress inducers such as tunicamycin and thapsigargin on TRAIL sensitivity of Ph1-ALL cell lines. Treatment with tunicamycin and thapsigargin upregulated the expressions of DRS both in both flow cytometric and real-time RT-PCR analysis. Moreover, treatment with tunicamycin and thapsigargin sensitized TRAIL-resistant Ph1-ALL cell lines to anti-leukemic activity of TRAIL. These observations suggest that the agents triggering ER-stress might sensitize leukemia cells to GVL effect. Less
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