DIFFERENT PATTERNS OF EPSTEIN-BARR VIRUS LATENCY IN ENDEMIC BURKITT LYMPHOMA (BL) LEAD TO DISTINCT VARIANTS WITHIN THE BL-ASSOCIATED GENE EXPRESSION SIGNATURE

Epstein-Barr virus (EBV) is present in all cases of endemic Burkitt Lymphoma (BL) but in few European/North American sporadic BLs. Gene expression arrays of sporadic tumours have defined a consensus BL profile within which tumours are classifiable as "molecular BL" (mBL). Where endemic BLs fall relative to this profile remains unclear, since they not only carry EBV but also display one of two different forms of virus latency. Here we use early passage BL cell lines from different tumours, and BL subclones from a single tumour, to compare EBV-negative cells with EBV-positive cells displaying either classical Latency I EBV infection (where EBNA1 is the only EBV antigen expressed from the wild-type EBV genome), or Wp-restricted Latency (where an EBNA2 gene-deleted virus genome broadens antigen expression to include the EBNA3A, 3B, 3C proteins and BHRF1). Expression arrays show that both types of endemic BL fall within the mBL classification. However, while EBV-negative and Latency I BLs show overlapping profiles, Wp-restricted BLs form a distinct subgroup, characterised by a detectable down-regulation of the germinal centre (GC)-associated marker Bcl6 and up-regulation of genes marking early plasmacytoid differentiation, notably IRF4 and BLIMP1. Importantly, these same changes can be induced in EBV-negative or Latency I BL cells by infection with an EBNA2-knockout virus. Thus we infer that the distinct gene profile of Wp-restricted BLs does not reflect differences in the identity of the tumour progenitor cell per se but differences imposed on a common progenitor by broadened EBV gene expression.