BCL6 breaks occur at different AID sequence motifs in Ig–BCL6 and non-Ig–BCL6 rearrangements

• Published in: Blood Vol. 121; no. 22; pp. 4551 - 4554
• Main Authors: Lu, Zhengfei, Tsai, Albert G., Akasaka, Takashi, Ohno, Hitoshi, Jiang, Yanwen, Melnick, Ari M., Greisman, Harvey A., Lieber, Michael R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30-05-2013; American Society of Hematology
• Subjects: Brief Report; Chromosome Breakage; Cytidine Deaminase - genetics; Cytidine Deaminase - metabolism; DNA-Binding Proteins - genetics; Gene Rearrangement, B-Lymphocyte - genetics; Germinal Center - pathology; Humans; Immunoglobulin Heavy Chains - genetics; Lymphoid Neoplasia; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - pathology; Precursor Cells, B-Lymphoid - enzymology; Precursor Cells, B-Lymphoid - pathology; Proto-Oncogene Proteins c-bcl-6; Translocation, Genetic - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-10-464958

BCL6 translocations are common in B-cell lymphomas and frequently have chromosomal breaks in immunoglobulin heavy chain (IgH) switch regions, suggesting that they occur during class-switch recombination. We analyze 120 BCL6 translocation breakpoints clustered in a 2156-bp segment of BCL6 intron 1, including 62 breakpoints (52%) joined to IgH, 12 (10%) joined to Ig light chains, and 46 (38%) joined to non-Ig partners. The BCL6 breaks in Ig–BCL6 translocations prefer known activation-induced cytosine deaminase (AID) hotspots such as WGCW and WRC (W = A/T, R = A/G), whereas BCL6 breaks in non-Ig rearrangements occur at CpG/CGC sites in addition to WGCW. Unlike previously identified CpG breaks in pro-B/pre-B-cell translocations, the BCL6 breaks do not show evidence of recombination activating gene or terminal deoxynucleotidyl transferase activity. Both WGCW/WRC and CpG/CGC breaks at BCL6 are most likely initiated by AID in germinal center B-cells, and their differential use suggests subtle mechanistic differences between Ig–BCL6 and non-Ig–BCL6 rearrangements.
•Chromosomal breaks in BCL6 translocations occur at two distinct DNA sequence motifs associated with AID activity.•Motif usage correlates with the type of BCL6 partner gene, suggesting mechanistic differences between Ig–BCL6 and non-Ig–BCL6 rearrangements.