The analysis of gene mutation acquisition and chemotherapy resistant mechanism by Hippo pathway of leukemia stem cells
| Project/Area Number |
17K09942
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Nippon Medical School |
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Principal Investigator |
Inokuchi Koiti 日本医科大学, 大学院医学研究科, 大学院教授 (10203267)
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| Co-Investigator(Kenkyū-buntansha) |
山口 博樹 日本医科大学, 医学部, 准教授 (90297937)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | 急性骨髄性白血病 / 白血病幹細胞 / Hippo pathway / Hippo Pathway / leukemic stem cell / YAP / mutation / lats |
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| Outline of Final Research Achievements |
In human myeloid leukemia cell lines, we confirmed that expression of MST1/2 and LATS1/2 increased and phosphorylation of YAP and TAZ was enhanced by a rise in cell density.
In leukemic stem cell (LSC) like cells of KG1a and KASUMI cell lines, and TF-1 cell line with MS-5 cell lines derived from mouse marrow interstitial cells, we confirmed that expression of MST1/2 and LATS1/2 increased and phosphorylation of YAP and TAZ was enhanced.
We analyzed these LSC and non-LSC-like fractionation using Genechip, but the activation of WNT/β-catenin and the TGF-β/Smads signal was not found.
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| Academic Significance and Societal Importance of the Research Achievements |
造血器腫瘍におけるHippo pathwayの機能を報告した研究はほとんどない。今回の解析結果を基盤にして白血病細胞内での遺伝子変異多様性獲得に至るプロセスを解明することに発展すると思われる。そしてHippo pathway によるLSCの維持機構やHippo pathwayの抑制によりLSC機能を失ったdriver 遺伝子変異を獲得した娘白血病細胞が再びLSC機能を獲得する機序が明らかになる可能性があり、最終的にこれらを標的とした分子標的薬が開発され再発/治療抵抗性AMLの治療成績向上に貢献できると思われる。
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Report
(4 results)
Research Products
(15 results)
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[Journal Article] Significance of FLT3-tyrosine kinase domain mutation as a prognostic factor for acute myeloid leukemia.2019
Author(s)
Sakaguchi M, Yamaguchi H, Kuboyama M, Najima Y, Usuki K, Ueki T, Oh I, Mori S, Kawata E, Uoshima N, Kobayashi Y, Kako S, Tajika K, Shono K, Kayamori K, Hagihara M, Kanda J, Uchiyama H, Kuroda J, Uchida N, Kubota Y, Kimura S, Kurosawa S, et al
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Journal Title
Int J Hematol
Volume: 110
Issue: 5
Pages: 566-574
DOI
Related Report
Peer Reviewed
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[Journal Article] Prognostic impact of low allelic ratio FLT3-ITD and NPM1 mutation in acute myeloid leukemia.2018
Author(s)
Sakaguchi M, Yamaguchi H, Najima Y, Usuki K, Ueki T, Oh I, Mori S, Kawata E, Uoshima N, Kobayashi Y, Kako S, Tajika K, Gomi S, Shono K, Kayamori K, Hagihara M, Kanda J, Uchiyama H, Kuroda J, Uchida N, Kubota Y, Kimura S, et al.
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Journal Title
Blood Advances
Volume: 2
Issue: 20
Pages: 2744-2754
DOI
Related Report
Peer Reviewed / Open Access
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