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発生工学的手法を用いた白血病関連転写因子TELの機能解析

Research Project

Project/Area Number 14657248
Research Category

Grant-in-Aid for Exploratory Research

Allocation TypeSingle-year Grants
Research Field Hematology
Research InstitutionDokkyo Medical University

Principal Investigator

三谷 絹子  獨協医科大学, 医学部, 教授 (50251244)

Co-Investigator(Kenkyū-buntansha) 和賀 一雄  獨協医科大学, 医学部, 講師 (00285917)
佐々木 光  獨協医科大学, 医学部, 助手 (60282638)
牧 和宏  獨協医科大学, 医学部, 助手 (50337391)
中村 裕一  獨協医科大学, 医学部, 講師 (20227896)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2003: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
KeywordsTEL / トランスジェニックマウス / ノックアウトマウス / コンディショナルマウス / ES / Creリコンビナーゼ / Lox-P配列
Research Abstract

1.TELトランスジェニックマウスの作製:野生型TEL及びそのドミナント・ネガティブHLH (helix-loop-helix)欠失変異体ΔHLHをGATA-1プロモーター下に発現するトランスジェニックマウスをそれぞれ3ラインずつ作製した。しかしながら、ウエスタン解析、免疫沈降法RT-PCR法により発現が確認されなかったため、別のラインを作製した。今後F1個体について、血算、骨髄の形態観察、各種サイトカインを用いた液体培養系での分化誘導実験、コロニー形成実験を行う予定である。さらに、マイクロアレイ解析により標的遺伝子を探索する。
2.TELノックアウトマウスの作製:マウスTEL遺伝子の第6エクソン〜第8エクソンの一部をneomycin耐性遺伝子およびIRES-GFP遺伝子で置き換えたターゲッティングベクターを構築し、相同組み換え体ESを1ライン得た。ヘテロマウスを用いてGFPを指標に胎生期のTELの発現部位を明らかにするとともに、ノックアウトマウスを用いて胎生致死のレスキュー実験を行う。
3.TELコンディショナルマウスの作製:マウスTEL遺伝子の第7エクソンの両端とそれに続くneomycin耐性遺伝子の端にLox-P配列を挿入したターゲッティングベクターを作製中である。これをES細胞に遺伝子導入し相同組み換え体を得る方針である。さらに、この相同組み換え体にpMC1-Creベクターを導入し、Lox-P配列を挟む領域を欠失させる。neomycin耐性遺伝子のみを削った(I型欠失)相同組み換えES細胞第7エクソンとneomycin耐性遺伝子を削った(II型欠失)相同組み換えES細胞を用いてキメラマウスの作製を行い、さらに交配によりヘテロマウス(I型欠失-TELflox/WT、II型欠失-TELΔ/WT)を得る。

Report

(3 results)
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (21 results)

All 2005 2004 Other

All Journal Article (9 results) Publications (12 results)

  • [Journal Article] Erratum, Author list correction for above paper2005

    • Author(s)
      Ichikawa M
    • Journal Title

      Nat Med 11

      Pages: 102-102

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The corepressor mSin3A regulates phosphorylation-induced activation, intranuclear location, and stability of AML1.2004

    • Author(s)
      Imai Y
    • Journal Title

      Mol Cell Biol 24

      Pages: 1033-1043

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Leukemia-related transcription factor TEL is negatively regulated through ERK-induced phosphorylation.2004

    • Author(s)
      Maki K
    • Journal Title

      Mol Cell Biol 24

      Pages: 3227-3237

    • Related Report
      2004 Annual Research Report
  • [Journal Article] AML1 is functionally regulated through p300-mediated acetylation on specific lysine residues.2004

    • Author(s)
      Yamaguchi Y
    • Journal Title

      J Biol Chem 279

      Pages: 279-304

    • Related Report
      2004 Annual Research Report
  • [Journal Article] AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis.2004

    • Author(s)
      Ichikawa M
    • Journal Title

      Nat Med 10

      Pages: 299-304

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Functional analysis of a dominant-negative DETS TEL/ETV6 isoform.2004

    • Author(s)
      Sasaki K
    • Journal Title

      Biochem Biophys Res Comm 317

      Pages: 1128-1137

    • Related Report
      2004 Annual Research Report
  • [Journal Article] TEL/AML1 shows dominant-negative effects over TEL as well as AML1.2004

    • Author(s)
      Gunji H
    • Journal Title

      Biochem Biophys Res Comm 322

      Pages: 623-630

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The transcriptionally active form of AML1 is required for hematopoietic rescue of the AML1-deficient embryonic para-aortic splanchnopleural (P-Sp) region.2004

    • Author(s)
      Goyama S
    • Journal Title

      Blood 104

      Pages: 3558-3564

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Molecular mechanisms of leukemogenesis by AML1/EVI-l.2004

    • Author(s)
      Mitani K
    • Journal Title

      Oncogene 23

      Pages: 4263-4269

    • Related Report
      2004 Annual Research Report
  • [Publications] Waga, K.: "Leukemia-related transcription factor TEL accelerates differentiation of Friend erythroleukemia cells."Oncogene. 22. 59-68 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Qiao, Y.: "Identification of a novel fusion gene, TTL, fused to ETV6 in acute lymphoblastic leukemia with t(12;13)(p13;ql4), and its implication in leukemogenesis."Leukemia. 17. 1112-1120 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Imai, Y.: "The corepressor mSin3A regulates phosphorylation-induced activation, intranuclear location, and stability of AML1."Mol.Cell.Biol.. 24. 1033-1043 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Maki, K.: "Leukemia-related transcription factor TEL is negatively regulated through ERK-induced phosphorylation."Mol.Cell.Biol.. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamaguchi, Y.: "AML1 is functionally regulated through p300-mediated acetylation on specific lysine residues."J Biol Chem.. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Ichikawa, M.: "AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis."Nat Med.. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Izutsu, K.: "The t(3;21) fusion product, AML1/Evi-1, blocks AML1-induced transactivation by recruiting CtBP"Oncogene. 21. 2395-2703 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tsurumi, S.: "N-ras and p53 gene mutations in Japanese patients with myeloproliferative disorders"Am J Hematol. 71. 131-133 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Arai, H.: "Functional regulation of TEL by p38-induced phosphorylation"Biochem Biophys Res Comm. 299. 116-125 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Imai, Y.: "Mutational analyses of the AML1 gene in patients with myelodysplastic syndrome"Leuk & Lymph. 43. 617-621 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Waga, K.: "Leukemia-related transcription factor TEL accelerates differentiation of Friend erythroleukemia cells"Oncogene. 22. 59-68 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakamura, F.: "Monocytic leukemia with CALM/AF10 rearrangement showing mediastinal emphysema"Am J Hematol. 72. 138-142 (2003)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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