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2019 Fiscal Year Final Research Report

Characiterization of ATL stem cell candidates in HBZ transgenic mouse model

Research Project

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Project/Area Number 16K09833
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Hematology
Research InstitutionNational Institute of Infectious Diseases

Principal Investigator

Mizukami Takuo  国立感染症研究所, 血液・安全性研究部, 室長 (60415487)

Project Period (FY) 2016-04-01 – 2020-03-31
KeywordsHTLV-1 / ATL / Tax / HBZ / モデルマウス / c-kit/SCF / 癌幹細胞 / 微小環境 (ニッチ)
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.

Free Research Field

血液内科学

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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Published: 2021-02-19  

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