| Project/Area Number |
21591223
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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 |
Hematology
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| Research Institution | Juntendo University |
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Principal Investigator |
TABE Yoko 順天堂大学, 医学部, 准教授 (70306968)
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| Co-Investigator(Kenkyū-buntansha) |
JIN Linhua 順天堂大学, 医学部, ポスドクフェロー (90531955)
IWABUCHI Kazuhisa 順天堂大学, 医療看護学部, 教授 (10184897)
TOMIKAWA Naoki (ICHIKAWA Naoki) 福島県立医科大学, 医学部, 助教 (80468587)
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| Project Period (FY) |
2009 – 2011
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| Project Status |
Completed (Fiscal Year 2011)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2011: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2009: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | 慢性骨髄性白血病 / イマチニブ / CXCR4 / Lyn / チロシンキナーゼ阻害剤 / 脂質ラフト / LYN / 骨髄微小環境 |
|---|
| Research Abstract |
p210Bcr-Abl tyrosine kinase inhibits CXCR4-mediated migration of chronic myeloid leukemia(CML) cells to bone marrow stroma. In turn, exposure of CML cells to a tyrosine kinase inhibitor(TKI) enhances migration of CML cells toward stromal cell layers and promotes nonpharmacological resistance to imatinib. Src-related kinase Lyn is known to interact with CXCL12/CXCR4 signaling and is directly activated by p210Bcr-Abl. TKI treatment under co-culture with mesenchymal stromal cells induced CXCR4 localization in the lipid raft fraction, which further co-localized with active phosphorylated form of Lyn(LynTyr396) in CML cells. Lyn inhibition or cholesterol depletion abrogated imatinib-induced migration. These findings demonstrate the critical role of lipid rafts in imatinib-induced CML migration and lodging within the bone marrow microenvironment through the compartmental changes of the multivalent CXCR4 and Lyn complex.
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