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To explore the role of p16 INK4a  as an intrinsic barrier to B cell transformation by EBV, we transformed primary B cells from an individual homozygous for a deletion in the  CDKN2A  locus encoding p16 INK4a  and p14 ARF . Using recombinant EBV-BAC viruses expressing conditional EBNA3C (3CHT), we developed a system that allows inactivation of EBNA3C in lymphoblastoid cell lines (LCLs) lacking active p16 INK4a  protein but expressing a functional 14 ARF -fusion protein (p14/p16). The  INK4a  locus is epigenetically repressed by EBNA3C – in cooperation with EBNA3A – despite the absence of functional p16 INK4a . Although inactivation of EBNA3C in LCLs from normal B cells leads to an increase in p16 INK4a  and growth arrest, EBNA3C inactivation in the p16 INK4a -null LCLs has no impact on the rate of proliferation, establishing that the repression of  INK4a  is a major function of EBNA3C in EBV-driven LCL proliferation. This conditional LCL system allowed us to use microarray analysis to identify and confirm genes regulated specifically by EBNA3C, independently of proliferation changes modulated by the p16 INK4a -Rb-E2F axis. Infections of normal primary B cells with recombinant EBV-BAC virus from which EBNA3C is deleted or with 3CHT EBV in the absence of activating ligand 4-hydroxytamoxifen, revealed that EBNA3C is necessary to overcome an EBV-driven increase in p16 INK4a  expression and concomitant block to proliferation 2–4 weeks post-infection. If cells are p16 INK4a -null, functional EBNA3C is dispensable for the outgrowth of LCLs.

Induction of p16INK4a Is the Major Barrier to Proliferation when Epstein-Barr Virus (EBV) Transforms Primary B Cells into Lymphoblastoid Cell Lines