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Development of a novel mechanism of T-ALL and its clinical application for the diagnosis and treatment.

Research Project

Project/Area Number 26460667
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Laboratory medicine
Research InstitutionChiba University

Principal Investigator

MATSUSHITA Kazuyuki  千葉大学, 医学部附属病院, 准教授 (90344994)

Co-Investigator(Kenkyū-buntansha) 野村 文夫  千葉大学, 医学部附属病院, 特任教授 (80164739)
星野 忠次  千葉大学, 大学院薬学研究院, 准教授 (90257220)
Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsT細胞性急性リンパ性白血病 / 質量分析 / モデルマウス / c-myc / PKM2 / PUF60/FIR / 急性リンパ性白血病 / 癌糖代謝 / c-myc / スプライシング / 急性Tリンパ性白血病 / 転写因子 / T細胞性急性リンパ性白血病 / c-myc遺伝子 / 臓器浸潤 / ノックアウトマウス / 機能解析
Outline of Final Research Achievements

The switch of pyruvate kinase (PK) M1 and PKM2 is pivotal for glucose metabolism in cancers. FUSE-binding protein (FBP)-interacting repressor (FIR) is a transcriptional repressor of the c-myc gene. This study investigated the thymic lymphoma tissues of mice and revealed that haplodeficiency of FIR significantly contributed to the splicing of PKM1 to PKM2 in mice thymic lymphoma using six-plex tandem mass tag (TMT) quantitative proteomic analysis in this mice model. TMT revealed 648 proteins that were up- or downregulated in mice thymic lymphoma tissues. Among them, PKM2 protein, but not PKM1, was upregulated in the thymic lymphoma as well as T-ALL. These results indicated that FIR haplodeficiency contributes the alternative splicing of PKM1 to PKM2 by partly inhibiting hnRNPA1 expression in the thymic lymphoma cells prior to T-ALL. Taken together, our findings suggest that FIR and its related spliceosomes are potential therapeutic targets for cancers, including T-ALL.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Research-status Report
  • 2014 Research-status Report
  • Research Products

    (22 results)

All 2016 2015 2014 Other

All Journal Article (13 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 13 results,  Open Access: 12 results,  Acknowledgement Compliant: 6 results) Presentation (6 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results) Remarks (2 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Anti-FIRs (PUF60) auto-antibodies are detected in the sera of early-stage colon cancer patients.2016

    • Author(s)
      Kobayashi S, Hoshino T, Hiwasa T, Satoh M, Rahmutulla B, Tsuchida S, Komukai Y, Tanaka T, Matsubara H, Shimada H, Nomura F, Matsushita K
    • Journal Title

      Oncotarget

      Volume: 7 Issue: 50 Pages: 82493-82503

    • DOI

      10.18632/oncotarget.12696

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Development and validation of the simultaneous measurement of four vitamin D metabolites in serum by LC-MS/MS for clinical laboratory applications2016

    • Author(s)
      Mamoru Satoh, Takayuki Ishige, Shoujiro Ogawa, Motoi Nishimura, Kazuyuki Matsushita, Tatsuya Higashi, Fumio Nomura
    • Journal Title

      Anal Bioanal Chem

      Volume: 408 Issue: 27 Pages: 7617-7627

    • DOI

      10.1007/s00216-016-9821-4

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Combined Secretomics and Transcriptomics Revealed Cancer-Derived GDF15 is Involved in Diffuse-Type Gastric Cancer Progression and Fibroblast Activation.2016

    • Author(s)
      Ishige T, Nishimura M, Satoh M, Fujimoto M, Fukuyo M, Semba T, Kado S, Tsuchida S, Sawai S, Matsushita K, Togawa A, Matsubara H, Kaneda A, Nomura F
    • Journal Title

      Sci Rep.

      Volume: 6 Issue: 1 Pages: 21681-21681

    • DOI

      10.1038/srep21681

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Exogenous expression of FIR demonstrated TP53-independent cell-killing effect and enhanced anti-tumor activity of carbon-ion beams.2015

    • Author(s)
      Kano M, Matsushita K, Rahmutulla B, Yamada S, Shimada H, Kubo S, Hiwasa T, Matsubara H, Nomura F
    • Journal Title

      Gene Ther

      Volume: 23(1) Issue: 1 Pages: 50-56

    • DOI

      10.1038/gt.2015.84

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Tacrolimus prevents laryngotracheal stenosis in an acute-injury rat model.2015

    • Author(s)
      Mizokami D, Araki K, Tanaka N, Suzuki H, Tomifuji M, Yamashita T, Matsushita K, Shimada H, Shiotani A.
    • Journal Title

      Laryngoscope

      Volume: Feb Issue: 6 Pages: 1-5

    • DOI

      10.1002/lary.25178

    • Related Report
      2015 Research-status Report 2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Haploinsufficiency of the c-myc transcriptional repressor FIR, as a dominant negative-alternative splicing model, promoted p53- dependent T-cell acute lymphoblastic leukemia progression by activating Notch1.2015

    • Author(s)
      Matsushita K, Kitamura K, Rahmutulla B,, Tanaka N, Ishige T, Satoh M, Hoshino T, Miyagi S, Mori T, Itoga S, Shimada H, Tomonaga T, Kito M, Nakajima-Takagi Y, Kubo S, Nakaseko C, Hatano M, Miki T, Matsuo M, Fukuyo M, Kaneda A, Iwama A and Nomura F.
    • Journal Title

      Oncotarget.

      Volume: 6 Pages: 5102-17

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Gene therapy of c-myc suppressor FUSE-binding protein-interacting repressor by Sendai virus delivery prevents tracheal stenosis.2015

    • Author(s)
      Mizokami D, Araki K, Tanaka N, Suzuki H, Tomifuji M, Yamashita T, Ueda Y, Shimada H, Matsushita K, Shiotani A.
    • Journal Title

      Plos One

      Volume: 10 Pages: 345-51

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sendai virus-mediated c-myc suppressor far-upstream element binding protein interacting repressor gene transfer suppresses head and neck squamous cell carcinoma.2015

    • Author(s)
      Tanaka N, Araki K, Mizokami D, Miyagawa Y, Yamashita T, Tomifuji M, Ueda Y, Inoue M, Hasegawa M, Matsushita K, Nomura F, Shimada H, Shiotani A.
    • Journal Title

      Gene Therapy

      Volume: 22 Pages: 297-304

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 選択的スプライシング変異による急性リンパ性白血病の進展機序とバイオマーカー探索.2015

    • Author(s)
      北村浩一, 松下一之, 小林宗平、石毛崇之、仙波利寿、木村明佐子、風見隆浩、糸賀 栄、別府美奈子、西村 基、佐藤 守、野村文夫.
    • Journal Title

      臨床病理

      Volume: 63 Pages: 1091-1102

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Gene therapy of c-myc suppressor FUSE-binding protein-interacting repressor by Sendai virus delivery prevents tracheal stenosis2015

    • Author(s)
      Mizokami D, Araki K, Tanaka N, Suzuki H, Tomifuji M, Yamashita T, Ueda Y,
    • Journal Title

      PLoS One

      Volume: 10 Issue: 1 Pages: 1-12

    • DOI

      10.1371/journal.pone.0116279

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Alternative splicing of DNA damage response genes and gastrointestinal cancers.2014

    • Author(s)
      Rahmutulla B, Matsushita K, Nomura F.
    • Journal Title

      World J Gastroenterol.

      Volume: 20 Issue: 46 Pages: 17305-13

    • DOI

      10.3748/wjg.v20.i46.17305

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Alternative splicing of FBP-interacting repressor coordinates c-Myc, P27Kip1/cyclinE and Ku86/XRCC5 expression as a molecular sensor for bleomycin-induced DNA damage pathway.2014

    • Author(s)
      Rahmutulla B, Matsushita K, Satoh M, Seimiya M, Tsuchida S, Kubo S, Shimada H, Ohtsuka M, Miyazaki M, Nomura F.
    • Journal Title

      Oncotarget

      Volume: 5 Pages: 2404-17

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Non-transmissible Sendai virus vector encoding c-myc suppressor FBP-interacting repressor for cancer therapy.2014

    • Author(s)
      Matsushita K, Shimada H, Ueda Y, Inoue M, Hasegawa M, Tomonaga T, Matsubara H, Nomura F.
    • Journal Title

      World J Gastroenterol.

      Volume: 20 Issue: 15 Pages: 4316-28

    • DOI

      10.3748/wjg.v20.i15.4316

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] Alternative splicing as biomarkers for DNA damage response: A novel mechanism of cancer progression through a single-nucleotides binding/multi-functional protein, FIR.2016

    • Author(s)
      Matsushita K. Rahmutulla B. Kitamura K, Beppu M. Nishimura M, Satoh M and Nomura F.
    • Organizer
      ICHG2016 [The 13th International Congress of Human Genetics
    • Place of Presentation
      京都国際会館(京都府京都市)
    • Year and Date
      2016-04-03
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] SAP155-mediated c-myc suppressor FBP-interacting repressor splicing variants are activated in colon cancer tissues2015

    • Author(s)
      Kajiwara T, Matsushita K, Nomura F.
    • Organizer
      日本癌学会シンポジウム
    • Place of Presentation
      金沢・石川県立音楽堂
    • Year and Date
      2015-01-21 – 2015-01-22
    • Related Report
      2014 Research-status Report
  • [Presentation] バイオバンク活用に向けた生体試料品質を考える国際標準化の動きと将来に向けての日本の取り組み2015

    • Author(s)
      松下一之
    • Organizer
      第2回JMACシンポジウム サテライトワークショップ
    • Place of Presentation
      東京・TKP東京駅前カンファレンスセンター
    • Year and Date
      2015-01-08
    • Related Report
      2014 Research-status Report
    • Invited
  • [Presentation] 選択的スプライシングからみた癌の診断・治療に役立つバイオマーカーの開発と基盤整備2014

    • Author(s)
      松下 一之, 野村 文夫
    • Organizer
      第61回日本臨床検査医学会学術集会
    • Place of Presentation
      福岡・国際コンベンションセンター
    • Year and Date
      2014-11-22 – 2014-11-23
    • Related Report
      2014 Research-status Report
  • [Presentation] 大腸癌診療の層別化を目指したMSI(microsatellite instability)、KRAS/NRAS/BRAF遺伝子検査および「がん予防相談外来」について.2014

    • Author(s)
      松下一之、石毛崇之、糸賀 栄、西村 基、澤井 摂、宇津野恵美、別府美奈子、野村文夫.
    • Organizer
      第59回日本人類遺伝学会、第21回日本遺伝子診療学会合同大会
    • Place of Presentation
      東京・船堀ホール
    • Year and Date
      2014-11-19 – 2014-11-22
    • Related Report
      2014 Research-status Report
  • [Presentation] Alternative splicing rather than haploinsufficiency of c-myc transcriptional repressor, FIR, promotes P53-dependent T-cell lymphoblastic leukemia progression.2014

    • Author(s)
      Matsushita K, Kitamura K, Bahityar R, Hoshino T, Iwama A, Shimada H, Tomonaga T, Kubo S, and Nomura F.
    • Organizer
      The 73rd annual meeting of the Japanese cancer association
    • Place of Presentation
      Yokohama・パシフィコ横浜
    • Year and Date
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Research-status Report
  • [Remarks] 千葉大学大学院医学研究院 分子病態解析学

    • URL

      http://www.m.chiba-u.ac.jp/class/moldiag/

    • Related Report
      2015 Research-status Report
  • [Remarks] 千葉大学大学院医学研究院分子病態解析学

    • URL

      http://www.m.chiba-u.ac.jp/class/moldiag/

    • Related Report
      2014 Research-status Report
  • [Patent(Industrial Property Rights)] 癌の予防剤および/または治療剤2015

    • Inventor(s)
      松下一之
    • Industrial Property Rights Holder
      千葉大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2015-03-05
    • Acquisition Date
      2016-12-16
    • Related Report
      2016 Annual Research Report

URL: 

Published: 2014-04-04   Modified: 2018-03-22  

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