Characiterization of ATL stem cell candidates in HBZ transgenic mouse model
| Project/Area Number |
16K09833
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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 | National Institute of Infectious Diseases |
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Principal Investigator |
Mizukami Takuo 国立感染症研究所, 血液・安全性研究部, 室長 (60415487)
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | HTLV-1 / ATL / Tax / HBZ / モデルマウス / c-kit/SCF / 癌幹細胞 / 微小環境 (ニッチ) / 成人T細胞白血病 (ATL) / 微小環境 (ニッチ ) / c-kit/SCFシグナリング / ATL stem cells / ATL癌幹細胞 / 微小環境 / transgenic mouse / ATL stem cell / Cancer stem cell / stem cell niche / 血液学 / がん / 免疫学 / ウイルス / 感染症 |
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| Outline of Final Research Achievements |
Human T cell leukemia virus-1 (HTLV-1) is a T cell tropic retrovirus that causes Adult T cell leukemia (ATL). ATL has worse prognosis than other T cell malignancies. We hypothesized the existence of chemotherapy resistant cancer stem cell in ATL. In previous studies, we have newly identified ATL stem cells (ATLSCs) candidate in the Tax transgenic (Tg) mouse model (Blood, 2009). In this study, we also found HBZ-Tg derived ATLSCs could not colonize and proliferate in the c-kit ligand, membrane bound SCF mutant mouse (Sl/Sld) and in the presence of SCF neutralizing antibody ACK2. These data clearly suggested that SCF-c-kit signaling is essential to colonize and initiating ATL in the mouse model. We also found CCL3, CCL4, IL-4, IL-9, and IL-10 are highly produced in the ATLSCs microenvironment. These data suggested that these cytokines environment synergistically regulate ATLSC function and leukemic niche.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究課題により，HTLV-1の２つの遺伝子TaxとHBZによって誘導されたATL細胞において，ATL癌幹細胞(ATLSCs)特性をもった細胞が存在していることin vivoで証明した。特に，共通して発現するc-kit/SCFシグナリングを抑制することで，ATLの進展を抑えることを明らかにし，ATLSCsを標的とすることで，新規治療法の開発に応用可能であることが示唆された。また，ATLSCsの維持に関し，特殊なサイトカイン環境が形成されていることを突き止め，このような微小環境を標的とした治療法の開発も可能であることを示した。
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Report
(5 results)
Research Products
(8 results)
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[Journal Article] Impact of the SCF signaling pathway on leukemia stem cell-mediated ATL initiation and progression in an HBZ transgenic mouse model.2016
Author(s)
Kuribayashi W, Takizawa K, Sugata K, Kuramitsu M, Momose H, Sasaki E, Hiradate Y, Furuhata K, Asada Y, Iwama A, Matsuoka M, Mizukami T*, Hamaguchi I*.
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Journal Title
Oncotarget
Volume: 7(32)
Issue: 32
Pages: 51027-51043
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Characterization of the ATL stem cell (ATLSC) niche and cytokine environment in an ATL mouse model.2018
Author(s)
Takuo Mizukami, Wakako Kuribayashi, Kiyoko Nojima, Yuki Hiradate, Eita Sasaki, Madoka Kuramitsu, Haruka Momose, Kenji Sugata, Atsushi Iwama, Masao Matsuoka, Isao Hamaguchi.
Organizer
第79回 日本血液学会
Related Report
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[Presentation] Characterization of the ATL stem cell (ATLSC) niche and cytokine environment in an ATL mouse model.2017
Author(s)
Takuo Mizukami, Wakako Kuribayashi, Kiyoko Nojima, Yuki Hiradate, Eita Sasaki, Madoka Kuramitsu, Haruka Momose, Kenji Sugata, Atsushi Iwama, Masao Matsuoka, Isao Hamaguchi.
Organizer
第79回 日本血液学会
Related Report
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