2006 Fiscal Year Final Research Report Summary
Establishment of new-therapy and analysis of mechanisms for resistance to apoptosis in poor-prognostic childhood leukemia
| Project/Area Number |
16390297
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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 | University of Yamanashi |
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Principal Investigator |
NAKAZAWA Shinpei University of Yamanashi, Department of Research Interdisciplinary Graduate School of Medicine and Engineering, Professor, 大学院医学工学総合研究部, 教授 (90090034)
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| Co-Investigator(Kenkyū-buntansha) |
SUGITA Kanji University of Yamanashi, Department of Research Interdisciplinary Graduate School of Medicine and Engineering, Associate Professor, 大学院医学工学総合研究部, 助教授 (60138055)
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)
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, Department of Research Interdisciplinary Graduate School of Medicine and Engineering, Research Fellow, 大学院医学工学総合研究部, 医学研究員 (90377531)
HONNA Hiroko University of Yamanashi, University of Yamanashi Hospital, Medical Staff, 医学部附属病院, 医員 (50377537)
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| Project Period (FY) |
2004 – 2006
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| Keywords | childhood leukemia / apoptosis / 11q23 translocation / cytotoxic ligand / t(17;19) / CD33 / LMO2 |
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| Research Abstract |
First, we analyzed anti-leukemic activity of TRAIL, one of cytotoxic ligand expressed on NK cells and CTLs, 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. Most of 11q23-rearranged ALL cell lines were moderately sensitive to FasL at levels comparable to other ALL cell lines. 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, since most of the patients' samples from t(17;19)-positive ALL were positive for cell surface expression of CD33, we analyzed the expression of CD33, one of the myeloid antigens occasionally expressed on ALL cells, on t(17;19)-positive ALL cell lines. CD33 was frequently expressed on t(17;
… More
19)-positive ALL cell lines, and introduction of E2A-HLF, a fusion transcription factor derived from t(17;19), into CD33-negative pre-B ALL cell lines using Zn-inducible expression vector induced CD33 expression, indicating that oncogenic fusion derived from translocation induces ectopic expression of CD33 on ALL. Moreover, mylotarg, a cytotoxic antibiotic calicheamicin-conjugated humanized anti-CD33 mAb, induced cell death in t(17;19)-positive ALL cell lines depending on the level of CD33 expression, suggesting that mylotarg could be a new therapeutic agent for t(17;19)-positive ALL.
Finally, since the PAR binding site in the promoter region of LMO2 gene has been reported to be critical for hematopoietic progenitor-specific expression of LMO2, which is an critical transcription regulator in hematopoiesis and is overexpressed in T-ALL with t(7;11) and t(11;14), we analyzed the expression of LMO2 in t(17;19)-positive ALL cells. E2A-HLF contains the DNA-binding domain of HLF, one of PAR transcription factors, suggesting that E2A-HLF might induce LMO2 expression in t(17;19)-positive ALL cells. Actually, t(17;19)-positive ALL cell lines overexpressed LMO2 and introduction of E2A-HLF into pre-B ALL cell lines using Zn-inducible expression vector induced LMO2 expression, suggesting that LMO2 might play an important role in the leukemogenesis of E2A-HLF. Biological significance of LMO2 in t(17;19)-positive ALL cells is now under investigation. Less
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Research Products
(10 results)
