Downregulation of the polyamine regulator spermidine/spermine N(1)-acetyltransferase by Epstein-Barr virus in a Burkitt's lymphoma cell line.

Transition of Akata Burkitt's lymphoma (BL) from a malignant to nonmalignant phenotype upon loss of Epstein-Barr virus (EBV) is evidence for a viral contribution to tumorigenesis despite the tight restriction of EBV gene expression in BL. Examination of global cellular gene expression in Akata subclones that retained or lost EBV identified spermidine/spermine N(1)-acetyltransferase (SAT1), an inducible enzyme whose catabolism of polyamines affects both apoptosis and cell growth, as one of a limited number of cellular genes downregulated by EBV. Re-infection of the EBV-negative Akata clone reduced SAT1 mRNA to a level comparable with the parental EBV-positive Akata. EBV-positive Akata cells demonstrated decreased SAT1 enzyme activity concomitant with altered intracellular polyamine constituents. Reduction of SAT1 in EBV-positive BL was a transcriptional effect. Forced expression of the viral BCL2 homologue, BHRF1, in an EBV-negative Akata clone reduced SAT1 mRNA. Thus, EBV repression of polyamine catabolism becomes a complementary alteration to dysregulated c-myc enhancement of polyamine synthesis in BL and favorable to BL lymphomagenesis.

A defective, rearranged Epstein-Barr virus genome in EBER-negative and EBER-positive Hodgkin's disease.

A ubiquitous herpesvirus that establishes life-long infection, the Epstein-Barr virus (EBV) has yielded little insight into how a single agent in general accord with its host can produce diverse pathologies ranging from oral hairy leukoplakia to nasopharyngeal carcinoma, from infectious mononucleosis to Hodgkin's disease (HD) and Burkitt's lymphoma. Its pathogenesis is further confounded by the less than total association of virus with histologically similar tumors. In other viral systems, defective (interfering) viral genomes are known to modulate outcome of infection, with either ameliorating or intensifying effects on disease processes initiated by prototype strains. To ascertain whether defective EBV genomes are present in HD, we examined paraffin-embedded tissue from 56 HD cases whose EBV status was first determined by cytohybridization for nonpolyadenylated EBV RNAs (EBERs). Using both standard polymerase chain reaction (PCR) and PCR in situ hybridization, we successfully amplified sequences that span abnormally juxtaposed BamHI W and Z fragments characteristic of defective heterogeneous (het) EBV DNA from 10 of 32 (31%) EBER-positive tumors. Of 24 EBER-negative HD, 8 yielded PCR products indicating presence of het EBV DNA. Two of these contained defective EBV in the apparent absence of the prototype virus. Of the 42 tumors analyzed for defective EBV by both PCR techniques, there was concordance of results in 38 (90%). Detection of defective EBV genomes with the potential to disrupt viral gene regulation suggests one mechanism for pathogenic diversity that may also account for loss of prototypic EBV from individual tumor cells.