Nonimmunoglobulin gene hypermutation in germinal center B cells

Somatic hypermutation is the most critical mechanism underlying the diversi fication of lg genes, Although mutation occurs specifically in B cells duri ng the germinal center reaction, it remains a matter of debate whether the mutation machinery also targets non-lg genes. We have studied mutations in the 5' noncoding region of the Bcl6 gene in different subtypes of lymphomas . We found frequent hypermutation in follicular lymphoma (25 of 59 = 42%) ( germinal center cell origin) and mucosa-associated lymphoid tissue (MALT) l ymphoma (19 of 45 = 42%) (postgerminal center), but only occasionally in ma ntle cell lymphoma (1 of 21 = 4.8%) (pregerminal center). Most mutations we re outside the motifs potentially important for transcription, suggesting t hey were not important in lymphomagenesis but may, like lg mutation, repres ent an inherent feature of the lymphoma precursor cells. Therefore, we inve stigated their normal cell counterparts microdissected from a reactive tons il. Bcl6 mutation was found in 13 of 24 (54%) clones from the germinal cent re but only in 1 of 24 (4%) clones from the naive B cells of the mantle zon e. The frequency, distribution, and nature of these mutations were similar to those resulting from the lg hypermutation process, The results show uneq uivocal evidence of non-lg gene hypermutation in germinal center B cells an d provide fresh insights into the process of hypermutation and lymphomagene sis. (C) 1999 by The American Society of Hematology.