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2008 Fiscal Year Annual Research Report

慢性骨髄性白血病におけるDNA修復エラーの分子病態と微少残存病変の制御の研究

Research Project

Project/Area Number 19591140
Research InstitutionTokyo Medical University

Principal Investigator

田内 哲三  Tokyo Medical University, 医学部, 准教授 (80281377)

KeywordsBCR-ABL / 耐性化 / DNA修復
Research Abstract

1)Saturation mutagenesis screenを用いたABLキナーゼ阻害剤の耐性化機序の解析:pMSCVレトロウイルスベクターにp210BCR-ABL cDNAを組み込み、mutS-,mutD5-,musT-E.coliをトランスフォームする。プラスミドDNAを精製後、ecotropic packaging cell line GP86にリン酸カルシウム沈降法を用いてトランスフェクトし10^5CFU/ml以上の高力価ウイルスを作成する。次にBCR-ABL cDNAにランダムに変異の入ったレトロウイルスベクターをIL-3依存性細胞株BaF3に感染させ、(1)Nilotinib、(2)AUY922、(3)Nilotinib+AUY922存在下にてIL-3非依存性増殖能を獲得した耐性化クローンをpick upした。各薬剤耐性化クローンよりDNAを抽出しPCRを用いて耐性化クローンにおけるBCR-ABL遺伝子の点突然変異の種類を解析し、ABLキナーゼ阻害剤の併用によるBCR-ABLの点突然変異の発生の抑制効果を検証した。Ni Iotinib 2μMにて耐性クローンはT3151、G334Vを検出。AUY922耐性クローンではWild type BCR-ABLのみであった。Nilotinib+AUY922では耐性クローンの検出は認めなかった。
2)In vivoにおけるAUY922+Nilotinibの併用効果の検討:Saturation mutagenesis screenをもちいて作成したBaF3細胞をヌードマウスに移植し(1)Nilotinib、(2)AUY922、(3)Nilotinib+AUY922の併用効果について解析した。Nilotinib+AUY922群では有意な生存期間の延長が確認された。ABLキナーゼ阻害剤とHSP90阻害剤との併用効果は耐性化クローンの出現を抑制するとともに、in vivoにおいても有効性が確認された。

  • Research Products

    (10 results)

All 2009 2008

All Journal Article (7 results) (of which Peer Reviewed: 7 results) Presentation (3 results)

  • [Journal Article] Compliance with taking imatinib mesylate in patients with chronic myeloid leukemia in the chronic phase.2009

    • Author(s)
      Kiguchi T
    • Journal Title

      Leukemia Research 33

      Pages: 506-508

    • Peer Reviewed
  • [Journal Article] Characteristics of dasatinib-and imatinib-resistant chronic myelogenous leukemia cells.2008

    • Author(s)
      Okabe S
    • Journal Title

      Clinical Cancer Research 14

      Pages: 6181-6186

    • Peer Reviewed
  • [Journal Article] Multicenter prospective trial evaluating the tolerability of imatinib for Japanese patients with chronic myelogenous leukemia in the chronic phase : does body weight matter?2008

    • Author(s)
      Kanda Y
    • Journal Title

      International Journal of Hematology 83

      Pages: 835-829

    • Peer Reviewed
  • [Journal Article] Relapse of chronic myeloid leukemia-chronic phase 14 years after allogeneic hematopoietic stem cell transplantation.2008

    • Author(s)
      Akahane D
    • Journal Title

      International Journal of Hematology 88

      Pages: 119-120

    • Peer Reviewed
  • [Journal Article] Activity of a novel Aurora kinase inhibitor against the T315I mutant form of BCR-ABL : in vitro and in vivo studies.2008

    • Author(s)
      Akahane D
    • Journal Title

      Cancer Science 99

      Pages: 1251-1257

    • Peer Reviewed
  • [Journal Article] Leukocytosis is linked to thrombosis at diagnosis, while JAK2 V617F mutation is associated with thrombos is during the course of essential thrombocythemia.2008

    • Author(s)
      Ohyashiki K
    • Journal Title

      International Journal of Hematology 87

      Pages: 446-448

    • Peer Reviewed
  • [Journal Article] Vitamin K2 induces autophagy and apoptosis simultaneously in leukemia cells.2008

    • Author(s)
      Yokoyama T
    • Journal Title

      Autophagy 4

      Pages: 629-640

    • Peer Reviewed
  • [Presentation] Combined effects of novel heat shock protein 90 inhibitor NVP-AUY922 and nilotinib against mutant forms of BCR-ABL.2008

    • Author(s)
      Tauchi T
    • Organizer
      50^<th> Annual Meeting of American Society of Hematology
    • Place of Presentation
      サンフランシスコ
    • Year and Date
      2008-12-08
  • [Presentation] The efficacy of histone deacetylase inhibitor, vorinostat against BCR-ABL positive leukemia cells include ABL kinase domain mutation in monotherapy and in combination with dasatinib.2008

    • Author(s)
      Okabe S
    • Organizer
      50^<th> Annual Meeting of American Society of Hematology
    • Place of Presentation
      サンフランシスコ
    • Year and Date
      2008-12-07
  • [Presentation] The analysis of HDAC inhibitor, vorinostat efficacy against wild type and BCR-ABL mutant positive leukemia cells in monotherapy and in combination with a pan-aurora kinase inhibitor, MK-0457.2008

    • Author(s)
      Okabe S
    • Organizer
      50^<th> Annual Meeting of American Society of Hematology
    • Place of Presentation
      サンフランシスコ
    • Year and Date
      2008-12-07

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Published: 2010-06-11   Modified: 2016-04-21  

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