2014 Fiscal Year Final Research Report
Elucidation of metabolic phenotypes of LICs and development of targeting therapy against LICs through Phd/VHL/HIF-1 regulatory system
Project/Area Number |
23689049
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Research Category |
Grant-in-Aid for Young Scientists (A)
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Allocation Type | Single-year Grants |
Research Field |
Hematology
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Research Institution | Keio University |
Principal Investigator |
TAKUBO Keiyo 慶應義塾大学, 医学部, 講師 (50502788)
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Project Period (FY) |
2011-04-01 – 2015-03-31
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Keywords | 造血幹細胞 / 白血病幹細胞 / 幹細胞ニッチ / メタボロミクス |
Outline of Final Research Achievements |
(1) We performed metabolomic analysis in hematopoietic stem cells (HSCs) and found that HSCs generate adenosine-5'-triphosphate by anaerobic glycolysis through a pyruvate dehydrogenase kinase (Pdk)-dependent mechanism. Loss of both Pdk isozymes attenuated HSC phenotypes including cell cycle. Thus, glycolytic metabolic status governed by Pdk acts as a cell cycle checkpoint that modulates HSCs. (2) Using a CML-like mouse model of myeloproliferative disease, we demonstrate that CML LICs can be divided into CD25(+)FcεRIα(-) Lineage marker (Lin)(-) Sca-1(+)c-Kit(+) (F(-)LSK) cells and CD25(-)F(-)LSK cells. The CD25(+)F(-)LSK cells had multilineage differentiation capacity, with a preference toward cytokine-producing mast cell commitment. The CD25(+)F(-)LSK cells exhibited higher LIC capacity. Our findings suggest that interleukin-2 derived from the microenvironment and CD25 expressed on CML LICs constitute a novel signaling axis that could be preferentially targeted in therapy for CML.
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Free Research Field |
血液学
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