REVERSAL OF EBV IMMORTALIZATION PRECEDES APOPTOSIS IN IL-6-INDUCED HUMAN B-CELL TERMINAL DIFFERENTIATION

Cell death in B cell terminal differentiation rapidly follows cell cyc le arrest in IL-6 differentiation of EBV-immortalized, lgG-bearing hum an lymphoblastoid cells in vitro. G1 arrest is now found to coincide w ith repression of EBNA2 and LMP1, two EBV genes essential for B cell t ransformation, without activation of the viral lytic cycle. IL-6-diffe rentiated B cells die by apoptosis, as evidenced by increases in Annex in V binding activity, PARP cleavage, and chromatin disorganization. E xpression of Mcl-1, a Bcl-2 family member, was specifically induced du ring IL-6 differentiation and downregulated during apoptosis. Thus, IL -6 reverses EBV immortalization and activates the terminal differentia tion program in IgG-bearing human B lymphoblastoid cells, including re gulation of an anti-apoptotic gene to coordinate differentiation, cell cycle arrest, and cell death.