DELETION VARIANTS WITHIN THE NF-KAPPA-B ACTIVATION DOMAIN OF THE LMP1ONCOGENE IN ACQUIRED IMMUNODEFICIENCY SYNDROME-RELATED LARGE-CELL LYMPHOMAS, IN PRELYMPHOMAS AND ATYPICAL LYMPHOPROLIFERATIONS

The latent membrane protein 1 (LMP1) oncogene of Epstein Barr virus (E BV) is expressed in tumor cells of acquired immunodeficiency syndrome (AIDS) related lymphomas, HIV-negative, EBV-associated malignant lymph oproliferations, nasopharyngeal carcinoma, as well as in reactive immu noblasts of infectious mononucleosis. Naturally occurring LMP1 deletio n variants (LMP1-del), characterized by clustered mutations and a dist inct 30 base pair deletion within the carboxy terminal domain of LMP1, essential for maximal NF-KB stimulation, have been identified in the same conditions. These variants prevail in AIDS-related lymphomas, and are associated with clinically aggressive behaviour in HIV-negative l ymphomas, and are frequent in prelymphomatous and reactive states. Fun ctional studies showing a growth advantage of cells infected by these variants may explain the accumulation of LMP1-del in these entities. I n the carboxy terminal NF-kappa B activation domain of LMP1, evidence of a hypervariable region close to the highly conserved 23 outermost a mino acids essential for malignant transformation, may reflect the nat ural selection of growth promoting variants involved in signalling pat hways. The prevalence of the same mutational pattern in AIDS-related l ymphoma as well as in hyperplastic reactive states and prelymphomas su pports the hypothesis that these variants confer st growth advantage m anifested under impaired cellular immunity.