2003 Fiscal Year Final Research Report Summary
Anti-leukemic activities of TNF-family ligands in childhood poor-prognostic leukemia
| Project/Area Number |
14570733
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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 (2003)
山梨医科大学 (2002) |
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Principal Investigator |
INUKAI Takeshi University of Yamanashi, 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, Hospital, Research Associate, 医学部附属病院, 助手 (70324192)
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| Project Period (FY) |
2002 – 2003
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| Keywords | leukemia / allo-SCT / cytotoxic T-lymphocytes / GVL-effect / TNF-family ligands / apoptosis |
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| Research Abstract |
Recently, allogeneic hematopoietic stem cell trasplantation (allo-SCT) is frequently performed to the children with poor prognostic acute lymphoblastic leukemia (ALL) such as Philadelphia chromosome (Ph1)-positive ALL and ALL with 11q23 translocations. A critical role for the immune system. termed graft-versus-leukemia (GVL) effect, in achieving a cure in patients with leukemia has been documented. Although the clinical observations strongly suggest a pivotal role of cytotoxic T lymphocytes (CTLs) in suppressing leukemias, the underlying effector mechanisms have not been well characterized. In this study, we have analyzed anti-leukemic effect of FasL and TRAIL, which are expressed on CTLs, on Ph1-positive leukemias and ALL with 11q23 translocations.
First, we have analyzed the in vitro effect of FasL on Ph1-positive leukemias, since allo-SCT is a potentially curative therapy against Ph1-positive leukemias. Both leukemic cell lines and primary cultured leukemia cells were basically resis
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tant to recombinant soluble FasL. In contrast, recombinant soluble TRAIL effectively induces apoptosis in most of Ph1-positive leukemia cell lines depending on the levels of cell surface DR4/DR5 expressions. Anti-leukemic effect of recombinant soluble TRAIL was also confirmed in the analysis using primary cultured cells. These results strongly suggest that TRAIL rather than FasL plays an important role in GVL effect on Ph1-positive leukemias.
Next, we have analyzed the in vitro FasL/TRAIL sensitivity of leukemias with 11q23 translocation, which are relatively resistant to allo SCT. Leukemic cell lines with 11q23 translocations were moderately sensitive to recombinant soluble FasL. In contrast to Ph1-positive leukemia, leukemia cell lines with 11q23 translocations cells with 11q23 translocations were resistant to both FasL and TRAIL. These results suggest that resistance to FasL and TRAIL could be one of the mechanisms for relatively poor outcome of allo SCT in patients with ALL with 11q23 translocations. Less
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[Publications] K.Uno, T.Inukai, N.Kayagaki, K.Goi, H.Sato, A.Nemoto, K.Takahashi, K.Kagami, N.Yamaguchi, H.Yagita, K.Okumura, T.Koyama, T.Suzuki, K.Sugita, S.Nakazawa: "TNF-related apoptosis-inducing ligand (TRAIL) frequently induces apoptosis in Philadelphia chromosome-positive leukemia cells"Blood. 101. 3658-3667 (2003)
Description
「研究成果報告書概要(欧文)」より
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[Publications] A.Inoue, M.Seidel, W.Wu, S.Kamizono, A.Ferrando, R.Bronson, H.Iwasaki, K.Akashi, A.Morimoto, J.Hitzler, T.Pestina, C.Jackson, R.Tanaka, M.Chong, P.McKinnon, T.Inukai, G.Grosveld, T.Look: "B. Slug, a highly conserved zinc finger transcriptional repressor, protects hematopoietic progenitor cells from radiation-induced apoptosis in vivo"Cancer Cell. 2. 279-288 (2002)
Description
「研究成果報告書概要(欧文)」より
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