| Project/Area Number |
16K08972
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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 |
Laboratory medicine
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| Research Institution | International University of Health and Welfare |
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Principal Investigator |
Kimura Asako 国際医療福祉大学, 成田保健医療学部, 講師 (40727939)
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| Co-Investigator(Kenkyū-buntansha) |
佐藤 守 千葉大学, 医学部附属病院, 特任准教授 (20401002)
野村 文夫 千葉大学, 医学部附属病院, 特任教授 (80164739)
松下 一之 千葉大学, 医学部附属病院, 准教授 (90344994)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | T細胞性急性リンパ芽球性白血病 / c-myc / ノックアウトマウス / LC-MS/MS / Tandem Mass Tag (TMT) / pyruvate kinase M2 / PK-M2 / histon / 癌代謝 / 蛋白質 / 癌 / 細胞・組織 |
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| Outline of Final Research Achievements |
FIR (FUSE binding protein -interacting repressor) is a transcriptional repressor of the c-myc gene and its heterozygous mice develop T-ALL (T cell acute lymphoblastic leukemia). In this study, Tandem Mass Tag (TMT) quantitative proteome analysis of thymic lymphoma tissues in T-ALL model mice revealed that 648 proteins, involved in regulation of transcriptional activity, DNA repair and replication, activation and proliferation of T cells, induction of apoptosis, and so on, were up- or downregulated in T-ALL mice compared to normal mice. Above all, pyruvate kinase (PK) M2 involved in tumor development and glucose metabolism was upregulated expressed at protein and mRNA levels significantly (around 2.5 times; p<0.002).And also it was confirmed FIR suppressed the expression of hnRNPA1 involved in the switching of PKM1 and PKM2. Our result suggested FIR would contribute to T-ALL development by participating in alternative splicing of PK in T-ALL developed due to FIR haploinsufficiency.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により、腫瘍の形成と糖代謝にかかわるPKM2が、FIRハプロ不全によるhnRNPA1発現増大により引き起こされるPKの選択的スプライシングの影響により増大していることが確認され、これらのタンパク質相互作用によるT-ALL発症の可能性という新たなメカニズムが見いだされた。今回の結果より、PKM2が新たなT-ALL の早期診断マーカー候補となり、これをターゲットとした新たな治療開発などに大きく貢献しうると期待される。
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