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

To gain an insight into the microenvironmental regulation of nuclear factor (NF)-kappa B 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-kappa B/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-kappa B, but Luc activity was synergistically upregulated by the combination of stromal cells and tumor necrosis factor (TNF)-alpha. Dehydroxymethylepoxyquinomicin (DHMEQ), a specific inhibitor of NF-kappa B DNA binding, rapidly induced the apoptosis of Ph+ALL cells, indicating that NF-kappa B is necessary for the growth and survival of these cells. However, the DHMEQ-induced suppression of NF-kappa B activity and the apoptosis of leukemia cells were attenuated by the presence of stromal cells and TNF-alpha. In NOD-SCID mice transplanted with NF-kappa B/Luc reporter-containing Ph+ALL cell lines and monitored periodically during the progression of the leukemia, murine TNF-alpha was significantly expressed in lesions in which the leukemia cells emitted a significant NF-kappa B signal. These results support the notion that TNF-alpha also triggers microenvironmental upregulation of NF-kappa B activity in vivo. Collectively, the results indicated that TNF-alpha-stimulated microenvironment may contribute to the survival and progression of Ph+ALL cells through the synergistic upregulation of NF-kappa B activity. (Cancer Sci 2011; 102: 2014-2021)