Open AccessBioimaging 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
Author(s) -
Tsai HuiJen,
Kobayashi Seiichiro,
Izawa Kiyoko,
Ishida Takaomi,
Watanabe Toshiki,
Umezawa Kazuo,
Lin ShengFung,
Tojo Arinobu
Publication year - 2011
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2011.02039.x
Subject(s) - stromal cell , tumor necrosis factor alpha , downregulation and upregulation , cancer research , leukemia , biology , tumor microenvironment , apoptosis , nf κb , cell culture , bone marrow , microbiology and biotechnology , immunology , chemistry , inflammation , tumor cells , biochemistry , genetics , gene
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)