Pharmacological inhibitors of NF-[kappa]B accelerate apoptosis in chronic lymphocytic leukaemia cells

Nuclear factor-kappaB (NF-[kappa]B) is a transcription factor that plays a critical role in the inappropriate survival of various types of malignant cells. Chronic lymphocytic leukaemia (CLL) is the most common B-cell malignancy in the Western world. Although overexpression and regulation of NF-[kappa]B has been described in CLL, its function remains unclear. Exposure of CLL cells to BAY117082 or Kamebakaurin, potent pharmacological inhibitors of the NF- [kappa]B pathway, accelerated apoptosis in approximately 70% of cases. Sensitivity to NF-[kappa]B pathway inhibitors was not related to the prognostic markers V sub(H) status, CD38 or Zap70 expression, or to the levels of nuclear NF-[kappa]B. Normal peripheral B cells were resistant to the apoptosis-inducing effects of these compounds. Cell death induced by the inhibitors was associated with activation of caspase-9 and -3, and loss of mitochondrial membrane polarization, but did not involve changes in the expression of Bcl-2 or Mcl-1. Inhibitors caused an increase in c-jun NH sub(2)- terminal kinase activity in CLL, but this did not appear to be important for apoptosis. Microarray analysis identified some potential novel NF-[kappa]B target genes, including interleukin-16- and the Bcl-2- related survival protein Bcl-w. These results demonstrate that a substantial proportion of CLL are dependent on NF-[kappa]B for enhanced survival and suggest that inhibition of NF-[kappa]B may have therapeutic potential.