Epstein-Barr virus nuclear antigen 2 (EBNA2) gene deletion is consistently linked with EBNA3A, -3B, and -3C expression in Burkitt's lymphoma cells and with increased resistance to apoptosis.
Most Epstein-Barr virus (EBV)-positive Burkitt's lymphomas (BLs) carry a wild-type EBV genome and express EBV nuclear antigen 1 (EBNA1) selectively from the BamHI Q promoter (latency I). Recently we identified a distinct subset of BLs carrying both wild-type and EBNA2 gene-deleted (transformation-defective) viral genomes. The cells displayed an atypical "BamHI W promoter (Wp)-restricted" form of latency where Wp (rather than Qp) was active and EBNA1, -3A, -3B, -3C, and -LP were expressed in the absence of EBNA2 or latent membrane proteins 1 and 2. Here we present data strongly supporting the view that the EBNA2-deleted genome is transcriptionally active in these cells and the wild-type genome is silent. Single-cell cloning of three parental Wp-restricted BL lines generated clones carrying either both viral genomes or the EBNA2-deleted genome only, never clones with the wild-type genome only. All rescued clones displayed the Wp-restricted form of latency characteristic of the parent line and retained the original parent cell phenotype. Interestingly, Wp-restricted parent lines and derived clones were markedly more resistant to inducers of apoptosis than standard latency I BL lines. Furthermore, in vitro infection of EBV-negative BL lines with an EBNA2 gene-deleted virus generated EBV-positive converts with Wp-restricted latency and a similarly marked apoptosis resistance. We postulate that, in the subset of BLs displaying Wp-restricted latency, infection of a tumor progenitor cell with an EBNA2 gene-deleted virus has provided that cell with a survival advantage through broadening antigen expression to include the EBNA3 proteins.
Kelly
Gemma L
GL
Cancer Research UK Institute for Cancer Studies, The University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
Milner
Anne E
AE
Tierney
Rosemary J
RJ
Croom-Carter
Debbie S G
DS
Altmann
Markus
M
Hammerschmidt
Wolfgang
W
Bell
Andrew I
AI
Rickinson
Alan B
AB
D000956:Antigens, Viral / Q000032:analysis*; D017209:Apoptosis; D002051:Burkitt Lymphoma / Q000473:pathology / Q000821:virology*; D002460:Cell Line; D045744:Cell Line, Tumor; D019309:Epstein-Barr Virus Nuclear Antigens / Q000032:analysis* / Q000235:genetics / Q000502:physiology; D016679:Genome, Viral; D006801:Humans; D014763:Viral Matrix Proteins / Q000235:genetics; D014764:Viral Proteins
D000956:Antigens, Viral; C402641:EBNA-2 protein, Human herpesvirus 4; C422762:EBNA-3B antigen; C498774:EBNA-3C, epstein-barr virus; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D014763:Viral Matrix Proteins; D014764:Viral Proteins