Downregulation of BLIMP1-alpha by the EBV oncogene, LMP1, disrupts the plasma cell differentiation program and prevents viral replication in B cells: implications for the pathogenesis of EBV-associated B cell lymphomas.

An important pathogenic event in Epstein-Barr virus (EBV)-associated lymphomas is the suppression of virus replication which would otherwise lead to cell death. Because virus replication in B cells is intimately linked to their differentiation towards plasma cells, we asked if the physiological signals which drive normal B cell differentiation are absent in EBV-transformed cells. We focussed on BLIMP1α, a transcription factor that is required for plasma cell differentiation and which is inactivated in diffuse large B cell lymphomas. We show that BLIMP1α expression is down-regulated following EBV infection of primary germinal centre (GC) B cells and that the EBV oncogene, latent membrane protein-1 (LMP1), is alone capable of inducing this down-regulation in these cells. Furthermore, the down-regulation of BLIMP1α by LMP1 was accompanied by a partial disruption of the BLIMP1α transcriptional programme, including the aberrant induction of MYC, the repression of which is required for terminal differentiation. Finally, we show that the ectopic expression of BLIMP1α in EBV-transformed cells can induce the viral lytic cycle. Our results suggest that LMP1 expression in progenitor GC B cells could contribute to the pathogenesis of EBV-associated lymphomas by down-regulating BLIMP1α in turn preventing plasma cell differentiation and induction of the viral lytic cycle.