| Project/Area Number |
20890097
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| Research Category |
Grant-in-Aid for Young Scientists (Start-up)
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| Allocation Type | Single-year Grants |
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| Research Field |
Hematology
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| Research Institution | Nagoya University |
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Principal Investigator |
MINAMI Yosuke Nagoya University, 医学部・附属病院, 医員 (60513752)
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| Project Period (FY) |
2008 – 2009
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| Project Status |
Completed (Fiscal Year 2009)
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| Budget Amount *help |
¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2009: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2008: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 白血病 / 幹細胞 / キナーゼ阻害剤 / BCR-ABL / mTORシグナル |
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| Research Abstract |
Recent studies suggest that leukemia stem cells (LSCs) are responsible for relapse of leukemia following conventional or targeted agents and that aberrant activation of mTOR signaling is involved in LSCs. To examine mechanisms of drug resistance in Ph-positive (Ph+) LSCs and seek strategies to overcome the resistance, Ph+ leukemia patient cells were serially xenotransplanted into immunodeficient NOG mice. Spleen cells derived from leukemic NOG mice were co-cultured with S17 stromal cells (Minami, et al., PNAS, 2008) and treated with imatinib and the mTOR inhibitor, everolimus (RAD001). While quiescent CD34+ cells were insensitive to imatinib in spite of BCR-ABL-dephosphorylation, substantial cell death including CD34+ population was induced by treatment with nM level of everolimus. In imatinib-resistant Ph+ leukemia cell lines harboring T315I-mutation, everolimus induced cell death with low IC50 values in PI-exclusion assays. We are also investigating detailed biomarkers during the cell death such as phospho-S6K and in vivo effects of theses drugs. These results imply that treatment with everolimus can overcome the resistance to imatinib in Ph+ LSCs or T315I-mutated cells.
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