S. Rothenberger et al., MOLECULAR AND FUNCTIONAL-ANALYSIS OF THE EPSTEIN-BARR-VIRUS LMP1 ONCOGENE PROMOTER IN LYMPHOPROLIFERATIVE DISEASES, Experimental hematology, 25(13), 1997, pp. 1326-1332
The expression of the Epstein-Barr virus (EBV) latent membrane protein
1 (LMP1) oncogene is tightly regulated by viral and cellular factors.
LMP1 is present in the majority of nasopharyngeal carcinoma tumor cel
ls and in Reed-Sternberg cells from Hodgkin's lymphoma, in which the o
nly EBV nuclear antigen detected is EBNA1. The aim of this study was t
o test whether mutations affecting LMP1 gene expression were present i
n lymphoproliferative disorders, and, if so, whether their presence co
rrelated with the clinical course of the disease. For this purpose we
characterized the LMP1 promoter region from seven cases including two
patients with aggressive Hodgkin's disease and two with atypical lymph
oproliferative syndromes. Our results show that the sequences -298 to
+29 relative to the transcription start site diverged up to 9.3% when
compared with the prototype EBV strain B95-8. The cAMP responsive-like
element (CRE), located at positions -37 to -44, was found to be mutat
ed in 3 of the 7 cases. Functional analysis of transfected human embry
onic kidney 293 cells using the firefly luciferase reporter gene revea
led that mutations within the CRE site led to a 70% mean decrease in r
eporter activity. Our analysis indicates that in lymphoproliferative d
isorders, naturally occurring LMP1 variants that exibit weak promoter
activity are still associated with clinically progressive disease.