2018 Fiscal Year Final Research Report
mTORC1 in osteoblastic niche regulates progression of acute myeloid leukemia.
Project/Area Number |
16H05131
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
General pharmacology
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Research Institution | Kanazawa University |
Principal Investigator |
Hinoi Eiichi 金沢大学, 薬学系, 准教授 (70360865)
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Research Collaborator |
Iezaki Takashi
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Project Period (FY) |
2016-04-01 – 2019-03-31
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Keywords | 白血病 |
Outline of Final Research Achievements |
Hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs) have self-renewal ability to maintain normal hematopoiesis and leukemia propagation, respectively. Recently, it has been reported that bone forming osteoblasts provide a microenvironment for LSCs and are implicated in pathogenesis and progression of leukemia as an osteoblastic niche in bone marrow. We here show a critical role of mTORC1 in regulating normal hematopoiesis and leukemia progression through its expression in osteoblasts in mice. Using a mouse models of acute myeloid leukemia (AML), we revealed that AML cells enhance the mTORC1 activity in osteoblasts in vivo and in vitro. Subsequent analyses determined that inactivation of Tsc1, a negative regulator of mTORC1, in osteoblasts results in a marked acceleration of AML. These findings highlight a critical role of mTORC1 in normal hematopoiesis and leukemia propagation, at least in part, through its expression in osteoblastic niche.
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Free Research Field |
薬理学
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Academic Significance and Societal Importance of the Research Achievements |
急性骨髄性白血病は、骨髄系造血細胞の異常増殖により引き起こされる造血器腫瘍であり、その治療には、抗がん剤を用いた寛解導入療法や造血幹細胞移植療法などが行われている。本研究では、造血幹細胞(白血病幹細胞)側のmTORC1活性ではなく、「ニッチ細胞側のmTORC1活性」による造血幹細胞(白血病幹細胞)の機能調節機構を解明した。これらの一連の研究成果は、造血幹細胞(白血病幹細胞)の機能異常に伴い誘発される各種血液疾患の発症・進展に対する効果的な制御法開発を指向する研究基盤になることが期待されることから、本研究成果の学術的意義および社会的意義は高い。
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