BCL-6

BCL-6 is a zinc-finger transcription factor that acts as a master regulator of the germinal center reaction. It represses genes involved in B-cell differentiation (e.g., BLIMP1/PRDM1), DNA damage response (e.g., p53, ATR, CHK1), and cell cycle checkpoints, allowing germinal center B cells to tolerate the physiologic DNA breaks from somatic hypermutation and class switch recombination while proliferating rapidly. Once B cells exit the germinal center and differentiate into plasma cells or memory B cells, BCL-6 expression is downregulated (largely via BLIMP1-mediated repression).

Clinical significance: BCL-6 translocations (commonly t(3;14) involving IGH, but also other partners) lead to deregulated/constitutive BCL-6 expression, contributing to lymphomagenesis by blocking terminal differentiation and suppressing DNA damage checkpoints, allowing accumulation of genetic lesions. BCL-6 rearrangements and overexpression are found in a significant subset of diffuse large B-cell lymphoma (DLBCL), particularly the germinal center B-cell-like (GCB) subtype, and in follicular lymphoma. Immunohistochemically, BCL-6 positivity (along with CD10 and MUM1) is used in the Hans algorithm to subclassify DLBCL into GCB vs. non-GCB (activated B-cell) subtypes, which has prognostic implications (GCB subtype generally has better prognosis). BCL-6 is also a marker for normal germinal center cells and angioimmunoblastic T-cell lymphoma (associated with T follicular helper cell origin, which also expresses BCL-6, CD10, PD-1, and CXCL13).

Therapeutically, BCL-6 inhibitors are being explored as targeted therapy for DLBCL given its critical oncogenic role.