NF-kappa B involvement in the activation of primary adult T-cell leukemia cells and its clinical implications

The HTLV-I provirus-encoded Tax protein induces NF-kappa B in Tax-transfect ed Jurkat T cells or HTLVL-I- infected T cells in vitro. Tax induction of N F-kappa B is presumed to be involved in proliferation and activation of pri mary leukemia cells in vivo. Recent studies have demonstrated that NF-kappa B activities in human T cells are mediated by at least four c-Rel-related DNA binding proteins - p50, p55, p75 and p85. We examined the significance of NF-kappa B induction in primary adult T cell leukemia cells and the indu ction kinetics of each of the four NF-kappa B species. Marked NF-kappa B ac tivity was detected using an electrophoretic mobility shift assay (EMSA) in the primary cells of patients with acute disease, but little activity was noted in the cells of chronic patients. NF-kappa B activity was enhanced in a time-dependent manner in acute type cells cultured with mitogen-freee me dium; there was no induction of activity in chronic type cells. UV crosslin king demonstrated all four species of NF-kappa B complex - high levels of p 50 and lower levels of p55 and p75, in acute type cells; chronic type cells showed only the p50. As a control, normal resting T cells similarly showed only p50; control cells showed little change in activity when cultured wit hout mitogenic stimulation, analogous to chronic type ATL, Northern blottin g revealed enhancement of c-rel (encoding p85) and KBF1 (encoding p50 and p 55) expression in acute type cells during culture, while there was no signi ficant enhancement of mRNAs in chronic type ATL cells or unstimulated norma l T cells. Northern blotting also revealed that Tax is upregulated at the m RNA level in acute- but not chronic-type cells during culture. Expression o f c-rel and KBF1 mRNAs in acute type cells appeared to be related to Tax mR NA expression. These results suggest that Tax is capable of inducing nuclea r expression of all four NF-kappa B species in primary ATL cells of acute t ype patients, with marked effects on p55, p75, and p85. Tax induction of NF -kappa B species is regulated, at least in part, at a pretranslational leve l involving increases in c-rel and KBF1 mRNA. (C) 1999 International Societ y for Experimental Hematology. Published by Elsevier Science Inc.