Association of Ig/BCL6 translocations with germinal center B lymphocytes in human lymphoid tissues: implications for malignant transformation.

Chromosomal translocations (CTs) between immunoglobulin (Ig) genes and the BCL6 proto-oncogene are frequently associated with diffuse large B-cell lymphomas (DLBCLs) and follicular lymphomas (FLs) and are implicated in the development of these lymphomas. However, whether Ig/BCL6 translocation per se is sufficient to drive malignant transformation is not clear. To understand the biology of Ig/BCL6-translocated cells prior to their malignant transformation, we developed a system capable of detecting 1 to 3 Igmu/BCL6 CT cells in 1 million mixed cells through the detection of chimeric Imu-BCL6E2 and BCL6E1-Cmu1 transcripts that reflect reciprocal Igmu/BCL6 translocations. The chimeric transcripts that existed in the vast majority of normal lymphoid tissues are due to Igmu/BCL6 CT and were not generated from trans-splicing. Both Imu-BCL6E2 and BCL6E1-Cmu1 transcripts were coexpressed in the same cell populations. The Ig/BCL6 recombination junctions themselves were isolated from B-cell subpopulations expressing the Imu-BCL6 transcripts. The appearance of Igmu/BCL6 CT was associated with cells expressing germinal center but not naive B-cell markers. This study shows that Ig/BCL6 translocations occur in germinal center-stage B cells in healthy humans, and that Ig/BCL6 CTs per se are not likely sufficient to cause the malignant transformation in the context of human B cells.