EBV-positive Hodgkin lymphoma is associated with suppression of p21(cip1/waf1 )and a worse prognosis

BACKGROUND: About 30-50% of Hodgkin lymphomas (HLs) harbor the Epstein-Barr virus (EBV), but the impact of EBV infection on clinical outcomes has been unclear. EBV-encoded small RNAs (EBERs) are presented in all EBV-infected cells, but their functions are still less understood. RESULTS: EBER1 was transfected into two HL cell lines, KMH2 and L428, and microarrays were used to screen for EBER1-induced changes. We found that EBER1 suppressed p21(cip1/waf1 )transcription in HL cell lines. In addition, positive regulators of p21(cip1/waf1 )transcription, such as p53, EGR1, and STAT1, were decreased. Suppression of p21(cip1/waf1 )in the EBER1(+ )HL cell lines was associated with increased resistance to histone deacetylase inhibitors or proteasome inhibitors, drugs known to cause apoptosis by increasing p21(cip1/waf1 )levels. On biopsy specimens, EBV(+ )HLs had weaker expression of both p21(cip1/waf1 )and active caspase 3. Clinically, suppression of p21(cip1/waf1 )in EBV(+ )HLs was associated with a worse 2-year disease-free survival rate (45% for EBV(+ )HLs vs. 77% for EBV(- )HLs, p = 0.002). CONCLUSION: Although the underlying mechanisms are still relatively unclear, EBER1 inhibits p21(cip1/waf1 )transcription and prevents apoptosis through down-regulation of p53, EGR1, and STAT1. The anti-apoptotic activity of EBER1 may be important in the rescue of Reed-Sternberg cells from drug-induced apoptosis and in the clinical behaviors of EBV(+ )HLs.