Analysis of stepwise genetic changes in an AIDS-related Burkitt's lymphoma

In this study, immunoglobulin variable (Ig V) region genes, c-myc re-arrang ement and sequence and p53 status were analyzed in clones derived from a Bu rkitt's lymphoma cell line (LAM) in which it was previously demonstrated th at Epstein-Barr virus (EBV) infection occurred late during lymphomagenesis. Such evidence was based on the finding that 2 groups of cellular clones, c haracterized by the same c-myc re-arrangement but different EBV-fused termi ni, were obtained from the LAM cell line. The Ig V gene sequences were iden tical for the 2 groups of clones with different EBV-fused termini. The Ig v ariable heavy (V-H) gene sequence displayed a substantial accumulation of p oint mutations (but no intraclonal diversification), whereas the productive Ig V lambda (V-lambda) gene sequence was virtually unmutated. Studies on t he Ig V kappa (V-kappa) locus suggested a receptor revision event (with a s witch from kappa to lambda chain production) prior to EBV infection. Likewi se, it was determined that the mutations observed in both p53 alleles and i n the re-arranged c-mye gene occurred before EBV infection. Based on these findings, we present a model for the various steps of lymphomagenesis. It i s proposed that stimulation by an antigen or a superantigen initially favor ed the clonal expansion and accumulation of other cytogenetic changes, incl uding those involved in receptor editing. These events occurred prior to or during the germinal center (GC) phase of B-cell maturation. Thereafter, po ssibly upon exit of the cells from the GC, EBV infection occurred, further promoting lymphomagenesis. (C) 2000 Wiley-Liss. Inc.