| Project/Area Number |
18390278
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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 |
Hematology
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| Research Institution | Mie University |
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Principal Investigator |
NOSAKA Tetsuya Mie University, Graduate School of Medicine, Professor (30218309)
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| Co-Investigator(Kenkyū-buntansha) |
KITAMURA Toshio The University of Tokyo, The Institute of Medical Science, Professor (20282527)
ONO Ryoichi Mie University, Graduate School of Medicine, Assistant Professor (40422414)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥17,580,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥1,980,000)
Fiscal Year 2007: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
Fiscal Year 2006: ¥9,000,000 (Direct Cost: ¥9,000,000)
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| Keywords | leukemic stem cell / 11q23 chromosomal translocation / MLL / infant leukemia / Ras / mouse bone marrow transplantation / retroviral vector / Hox / 白血病肝細胞 / Raf / MAPK / STAT5 |
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| Research Abstract |
A variety of reciprocal 11q23 translocations generating fusions of MLL(Mixed Lineage Leukemia) with partner genes are frequently found in infant acute leukemia. However, little has been clarified regarding the pathway through which MLL fusion proteins lead to leukemia. We have recently reported the two-step leukemogenesis by MLL fusion proteins in mice models(Ono R, et. al. Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis. J. Clin. Invest 115, 919-929, 2005 ; selected as one of the highlight papers in the April 2005 issue of the Nature Reviews/Cancer). By comparing the effects of two kinds of FLT3 mutants, and constitutively active mutant molecules of Ras, Raf, and STATS, we first identified Ras/Raf/MAPK as synergistic collaborative pathway for MLL fusion proteins to induce acute leukemia. Furthermore, expression of Hoxa9, one of the upregulated molecules in MLL-related human leukemia, and Ras activation were found to recapitulate MLL-fusion-mediated acute leukemia in mice. Hoxa9 is considered to contribute to confer self-renewal activity on leukemic cells, and Ras activation is inferred to induce proliferation of the leukemic cells.
Thus this study unveiled the molecular mechanism of MLL-fusion-mediated leukemogenesis, and may help develop the MLL-fusion-targeted therapy in future.
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