BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance

DOI PDF 被引用文献2件
  • Mateusz Koptyra
    From the Department of Microbiology and Immunology, School of Medicine and the Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA; the Department of Immunology, The Medical University of Warsaw, Poland; and the Department of Molecular Genetics, University of Lodz, Poland.
  • Rafal Falinski
    From the Department of Microbiology and Immunology, School of Medicine and the Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA; the Department of Immunology, The Medical University of Warsaw, Poland; and the Department of Molecular Genetics, University of Lodz, Poland.
  • Michal O. Nowicki
    From the Department of Microbiology and Immunology, School of Medicine and the Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA; the Department of Immunology, The Medical University of Warsaw, Poland; and the Department of Molecular Genetics, University of Lodz, Poland.
  • Tomasz Stoklosa
    From the Department of Microbiology and Immunology, School of Medicine and the Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA; the Department of Immunology, The Medical University of Warsaw, Poland; and the Department of Molecular Genetics, University of Lodz, Poland.
  • Ireneusz Majsterek
    From the Department of Microbiology and Immunology, School of Medicine and the Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA; the Department of Immunology, The Medical University of Warsaw, Poland; and the Department of Molecular Genetics, University of Lodz, Poland.
  • Margaret Nieborowska-Skorska
    From the Department of Microbiology and Immunology, School of Medicine and the Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA; the Department of Immunology, The Medical University of Warsaw, Poland; and the Department of Molecular Genetics, University of Lodz, Poland.
  • Janusz Blasiak
    From the Department of Microbiology and Immunology, School of Medicine and the Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA; the Department of Immunology, The Medical University of Warsaw, Poland; and the Department of Molecular Genetics, University of Lodz, Poland.
  • Tomasz Skorski
    From the Department of Microbiology and Immunology, School of Medicine and the Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA; the Department of Immunology, The Medical University of Warsaw, Poland; and the Department of Molecular Genetics, University of Lodz, Poland.

書誌事項

公開日
2006-07-01
DOI
  • 10.1182/blood-2005-07-2815
公開者
American Society of Hematology

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説明

<jats:p>Mutations in the BCR/ABL kinase domain play a major role in resistance to imatinib mesylate (IM). We report here that BCR/ABL kinase stimulates reactive oxygen species (ROS), which causes oxidative DNA damage, resulting in mutations in the kinase domain. The majority of mutations involved A/T→G/C and G/C→A/T transitions, a phenotype detected previously in patients, which encoded clinically relevant amino acid substitutions, causing IM resistance. This effect was reduced in cells expressing BCR/ABL(Y177F) mutant, which does not elevate ROS. Inhibition of ROS in leukemia cells by the antioxidants pyrrolidine dithiocarbamate (PDTC), N-acetylcysteine (NAC), and vitamin E (VE) decreased the mutagenesis rate and frequency of IM resistance. Simultaneous administration of IM and an antioxidant exerted better antimutagenic effect than an antioxidant alone. Therefore, inhibition of ROS should diminish mutagenesis and enhance the effectiveness of IM. (Blood. 2006;108:319-327)</jats:p>

収録刊行物

  • Blood

    Blood 108 (1), 319-327, 2006-07-01

    American Society of Hematology

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