An investigation of the regulation of BLIMP1 by the epstein-barr virus in B cells

[摘要] BLIMP1 is a transcription factor that regulates plasma cell differentiation. In this thesis I explore the regulation of BLIMP1 by EBV and by the EBV oncogene, latent membrane protein-1 (LMP1). In chapter 3, I show that BLIMP1α is down-regulated following the infection of germinal centre (GC) B cells with EBV. I also show that the ectopic expression of LMP1, was sufficient to decrease BLIMP1α expression in these cells and was accompanied by a partial disruption of the BLIMP1α transcriptional programme, including the aberrant induction of C-MYC. In chapter 4, I show that the ectopic expression of BLIMP1α in EBV-transformed cells and in EBV-positive Burkitt’s lymphoma cells can induce the viral lytic cycle. Chapter 5 provides evidence that LMP1 drives a reciprocal regulatory loop in GC B cells involving BLIMP1α and C-MYC which ultimately leads to the activation of C-MYC and the repression of BLIMP1α. Finally, in chapter 6, I present preliminary evidence showing that the BLIMP1β isoform is up-regulated in EBV-transformed B cells and in Hodgkin’s lymphoma cells; an effect which appeared to be mediated by hypomethylation of the BLIMP1β specific promoter. In summary, my results suggest that EBV can subvert normal B cell differentiation by modulating expression of the different BLIMP1 isoforms. These effects appear to be important not only for the regulation of the viral lytic cycle in B cells, but also potentially for the block in differentiation characteristic of EBV-associated B cell lymphomas.

[发布机构] University:University of Birmingham;Department:Institute of Cancer Studies

[关键词] R Medicine;R Medicine (General)