| Project/Area Number |
16K19205
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Laboratory medicine
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| Research Institution | Tokyo University of Technology |
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Principal Investigator |
OKUHASHI Yuki 東京工科大学, 医療保健学部, 助教 (90734715)
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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 |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 白血病 / シグナル伝達 / Notchシグナル / siRNA / CRISPR/cas9 / PTEN / 偽遺伝子 / シグナル伝達系 / ゲノム編集 / 臨床血液学 / 癌 |
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| Outline of Final Research Achievements |
Notch signaling is crucial for the growth of leukemia cells. We reported the effects of γ-secretase inhibitors (GSIs), which block Notch activation, on the growth of leukemia cells. GSIs suppressed the growth through induction of apoptosis in most of cell lines. Conversely, the growth of some cell lines were promoted by GSI treatment. I investigated the mechanisms focusing on the crosstalk between NOTCH1 and NOTCH2 signaling in leukemia cells.
Using siRNA-mediated knockdown experiments, we found that not only NOTCH1 knockdown but also NOTCH2 knockdown affected the growth of these NOTCH1-mutated, NOTCH2-unmutated T-lymphoblastic leukemia cell lines. The growth suppression by NOTCH2 knockdown did not involve the suppression of MYC expression, which was suppressed by NOTCH1 knockdown. We also found the crosstalk between NOTCH1 and NOTCH2 in Jurkat cell line, which suggests that Jurkat might have reciprocally compensating system between two NOTCH. It might cause the resistance to GSIs.
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| Academic Significance and Societal Importance of the Research Achievements |
Notch1だけでなくNotch2が白血病細胞の増殖に関与している可能性が本研究から明らかになった。また、PTEN遺伝子欠損細胞を作成し、Notch阻害剤への効果や他のシグナル伝達系へ及ぼす影響を明らかにする研究は本研究が世界初である。
本研究成果により、白血病細胞におけるNotchシグナル伝達系の分子機序が明らかになった。これにより、症例ごとの白血病幹細胞の特性を検出する分子生物学的検査法や症例に応じた分子標的薬を選択することが可能になる。将来は本研究の結果をふまえ、白血病幹細胞に特異的で、副作用が少ない分子標的治療の開発とその検討研究が予想される。
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