BCL-6 mutations in normal germinal center B cells: Evidence of somatic hypermutation acting outside Ig loci

摘要

The molecular mechanism involved in the process of antigen-drivensomatic hypermutation of Ig genes is unknown, but it is commonlybelieved that this mechanism is restricted to the Ig loci. B celllymphomas commonly display multiple somatic mutations clustering in the5′-regulatory region of BCL-6, a proto-oncogene encoding for aPOZ/Zinc finger transcriptional repressor expressed in germinalcenter (GC) B cells and required for GC formation. To determine whetherBCL-6 mutations represent a tumor-associated phenomenon or reflect aphysiologic mechanism, we screened single human tonsillar GC B cellsfor mutations occurring in the BCL-6 5′-noncoding region and in the Igvariable heavy chain sequences. Thirty percent of GC B cells, but notnaive B cells, displayed mutations in the 742 bp region analyzed withinthe first intron of BCL-6 (overall frequency: 5 ×10−4/bp). Accordingly, an expanded survey in lymphoidmalignancies showed that BCL-6 mutations are restricted to B celltumors displaying GC or post-GC phenotype and carrying mutated Igvariable heavy chain sequences. These results indicate that the somatichypermutation mechanism active in GC B cells physiologically targetsnon-Ig sequences.