2013 Fiscal Year Final Research Report
Mechanisms involved in degradation of activated thyrosine kinase mutants induced by anti-cancer drugs and its clinical application
| Project/Area Number |
24790966
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Hematology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
NAGAO Toshikage 東京医科歯科大学, 医学部附属病院, 助教 (10622798)
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| Project Period (FY) |
2012-04-01 – 2014-03-31
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| Keywords | 造血器腫瘍 / Jak2-V617F / MYD88 |
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| Research Abstract |
To explore the mechanisms that are involved in the enhanced cell survival and proliferation induced by the activated Jak2 mutant Jak2-V617F, known to be deeply linked to pathogenesis of some myeloid malignancies, we examined newly established Jak2-V617 bearing leukemic cell line PVTL-1. Consequently, not only Jak2-V617F but also the Src family kinase Lyn was constitutively activated and phosphorylated various kinds of intracellular signaling molecules. Additionally, it was suggested that apoptosis may be suppressed in PVTL-1 cells through inactivation of GSK3 by Lyn as well as Jak2-V617F and that activation of the mTOR/p70S6K/4EBP1 pathway may mediate proliferation signaling from Jak2-V617F and Lyn. On the other hand, we identified a novel mutation of TLRs/IL-1R associated adaptor protein MYD88, MYD88-L265-RPP, from the clinical sample of a Waldenstrom's macroglobulinemia case. Cells expressing this mutant showed significant activation of the NF-kB pathway.
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[Remarks] BioMed サーカス, 研究論文ハイライト, 執筆者自身による研究論文レビュー, 長尾俊景, 三浦修『Jak2-V617F とLyn からのGSK3 およびmTOR 経路を介した生存と増殖のシグナル伝達機構の新規樹立Jak2-V617F 陽性AML 細胞株PVTL-1 における解析』, 2014年2月21日
