• Open Access

Bioimaging analysis of nuclear factor-κB activity in Philadelphia chromosome-positive acute lymphoblastic leukemia cells reveals its synergistic upregulation by tumor necrosis factor-α-stimulated changes to the microenvironment

Authors

  • Hui-Jen Tsai,

    1. Division of Molecular Therapy, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
    2. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung
    3. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
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  • Seiichiro Kobayashi,

    1. Division of Molecular Therapy, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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  • Kiyoko Izawa,

    1. Division of Molecular Therapy, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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  • Takaomi Ishida,

    1. Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo
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    • Present address: Center for Asian Infectious Disease, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

  • Toshiki Watanabe,

    1. Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo
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  • Kazuo Umezawa,

    1. Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Japan
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  • Sheng-Fung Lin,

    1. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung
    2. Division of Hematology/Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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  • Arinobu Tojo

    Corresponding author
    1. Division of Molecular Therapy, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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To whom correspondence should be addressed.
E-mail: a-tojo@ims.u-tokyo.ac.jp

Abstract

To gain an insight into the microenvironmental regulation of nuclear factor (NF)-κB activity in the progression of leukemia, we established a bioluminescent imaging model of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) cells transduced with a NF-κB/luciferase (Luc) reporter and cocultured with murine stromal cells and cytokines. Stromal cells alone did not augment Luc activity, taken as an index of NF-κB, but Luc activity was synergistically upregulated by the combination of stromal cells and tumor necrosis factor (TNF)-α. Dehydroxymethylepoxyquinomicin (DHMEQ), a specific inhibitor of NF-κB DNA binding, rapidly induced the apoptosis of Ph+ALL cells, indicating that NF-κB is necessary for the growth and survival of these cells. However, the DHMEQ-induced suppression of NF-κB activity and the apoptosis of leukemia cells were attenuated by the presence of stromal cells and TNF-α. In NOD-SCID mice transplanted with NF-κB/Luc reporter-containing Ph+ALL cell lines and monitored periodically during the progression of the leukemia, murine TNF-α was significantly expressed in lesions in which the leukemia cells emitted a significant NF-κB signal. These results support the notion that TNF-α also triggers microenvironmental upregulation of NF-κB activity in vivo. Collectively, the results indicated that TNF-α-stimulated microenvironment may contribute to the survival and progression of Ph+ALL cells through the synergistic upregulation of NF-κB activity. (Cancer Sci 2011; 102: 2014–2021)

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