DELETION VARIANTS WITHIN THE NF-KAPPA-B ACTIVATION DOMAIN OF THE LMP1ONCOGENE PREVAIL IN ACQUIRED IMMUNODEFICIENCY SYNDROME-RELATED LARGE-CELL LYMPHOMAS AND HUMAN IMMUNODEFICIENCY VIRUS-NEGATIVE ATYPICAL LYMPHOPROLIFERATIONS

This sequencing study of 17 acquired immunodeficiency syndrome-related lymphomas (9 primary brain, 8 systemic) and 8 human immunodeficiency virus-negative atypical lymphoproliferations expressing large amounts of the latent membrane protein 1 (LMP1) of Epstein-Barr virus was perf ormed to characterize the carboxy terminal NF-kappa B activation domai n of LMP1 at the molecular level in an immunocompromised host. in-fram e deletions within the NF-kappa B activation domain were identified in all but 2 primary brain lymphomas, 4 systemic lymphomas, and 4 atypic al lymphoproliferations, ie, in 60% of cases. In addition, non silent point mutations (range 1 to 5, mean 3.3) were detected in all cases. A lthough all changes occurred within the first 100 nucleotides of the c arboxy terminal NF-kappa B activation domain-a critical sequence for t he protein half-life-not a single point mutation was found in the rema ining 62 nucleotides, necessary for malignant transformation. Such a c lustering of nonrandom sequence variations, associated with a high onc oprotein expression in immunocompromised hosts, suggests that this par t of the LMP1 oncogene behaves as a hypervariable region with natural selection of growth-promoting variants through prolongation of the pro tein half-life. (C) 1996 by The American Society of Hematology.