dehydroxymethylepoxyquinomicin and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

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.

Topics: Animals; Antineoplastic Agents; Benzamides; Bone Marrow; Cell Line, Tumor; Cyclohexanones; Disease Progression; Gene Expression Regulation, Leukemic; Genes, Reporter; Humans; Imatinib Mesylate; Luminescent Measurements; Mice; Neoplasm Proteins; NF-kappa B; Piperazines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Recombinant Fusion Proteins; Spleen; Stromal Cells; Transgenes; Transplantation, Heterologous; Tumor Burden; Tumor Microenvironment; Tumor Necrosis Factor-alpha