Nuclear factor-κB dimer exchange promotes a p21waf1/cip1 superinduction response in human T leukemic cells

The nuclear factor-kappa B (NF-kappa B)/Rel transcription factors are recognized as critical apoptosis regulators. We reported previously that NF-kappa B contributes to chemoresistance of CEM human T leukemic cells in part through its ability to induce p21(waf1/cip1). Here, we provide evidence that sequential NF-kappa B-activating signals induce heightened NF-kappa B DNA binding and p21(waf1/cip1) induction in CEM and additional T leukemic cell lines. This response arises from exceedingly low basal expression of the p105/p50 NF-kappa B subunit encoded by the NFKB1 gene in these cell lines. An initial NF-rB activation event enhances the recruitment of p65 and ELF1 to the NFKB1 promoter, leading to p65- and ELF1-dependent synthesis of p105/p50, which promotes an exchange of NF-rB complexes to p50-containing complexes with an increased DNA-binding activity to certain NF-rB target elements. Subsequent stimulation of these cells with an anticancer agent, etoposide, results in augmented NF-kappa B-dependent p21(waf1/cip1) induction and increased chemoresistance of the leukemia cells. Thus, we propose that low basal NFKB1 expression coupled with sequential NF-kappa B activation events can promote increased chemoresistance in certain T leukemic cells.