Deletion Variants within the NF-kB Activation Domain of the LMP1 Oncogene in Acquired Immunodeficiency Syndrome-Related Large Cell Lymphomas, in Prelymphomas and Atypical Lymphoproliferations

Abstract

The latent membrane protein 1 (LMP1) oncogene of Epstein Barr virus (EBV) is expressed in tumor cells of acquired immunodeficiency syndrome (AIDS) related lymphomas, HIV-negative, EBV-associated malignant lymphoproliferations, nasopharyngeal carcinoma, as well as in reactive immunoblasts of infectious mononucleosis. Naturally occurring LMP1 deletion variants (LMP1 -del), characterized by clustered mutations and a distinct 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 lymphomas, and are frequent in prelymphomatous and reactive states. Functional studies showing a growth advantage of cells infected by these variants may explain the accumulation of LMP1-del in these entities. In the carboxy terminal NF-kB activation domain of LMP1, evidence of a hypervariable region close to the highly conserved 23 outermost amino acids essential for malignant transformation, may reflect the natural selection of growth promoting variants involved in signalling pathways. The prevalence of the same mutational pattern in AIDS-related lymphoma as well as in hyperplastic reactive states and prelymphomas supports the hypothesis that these variants confer a growth advantage manifested under impaired cellular immunity.

Key Words:

• NF-kB activation
• LMP1 oncogene
• AIDS-related large cell lymphoma
• prelymphoma