B Cell Lymphoma 6 (BCL6): A Conserved Regulator of Immunity and Beyond

Abstract

B cell lymphoma 6 (BCL6) is a conserved multi-domain protein that functions principally as a transcriptional repressor. This protein regulates many pivotal aspects of immune cell development and function. BCL6 is critical for germinal center (GC) formation and the development of high-affinity antibodies, with key roles in the generation and function of GC B cells, follicular helper T (Tfh) cells, follicular regulatory T (Tfr) cells, and various immune memory cells. BCL6 also controls macrophage production and function as well as performing a myriad of additional roles outside of the immune system. Many of these regulatory functions are conserved throughout evolution. The BCL6 gene is also important in human oncology, particularly in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), but also extending to many in other cancers, including a unique role in resistance to a variety of therapies, which collectively make BCL6 inhibitors highly sought-after.

Keywords: B cell; BCL6; T cell; cancer; germinal center; lymphoma; macrophage; repressor; transcription factor.

Figure 1

Structure and function of the BCL6 protein. (A). Domains of the BCL6 protein: BTB (light blue), RD2/PEST (blue), and ZF (dark blue, with striping for fingers not involved in DNA binding). Above is a schematic representation of the structure of each domain along with their interacting proteins, including co-repressors (pink) and associated transcriptional regulators (orange) and DNA modifying proteins (green), with sites of ubiquitination (Ub), phosphorylation (P), and acetylation (Ac) indicated (brown). (B). Major molecular function(s) of each domain. (C). Biological roles mapped to the molecular functions, with proven connections shown as filled boxes and assumed ones as unfilled boxes. Abbreviations: BTB: broad complex/tram track/bric-a-brac; RD2: repression domain 2; PEST: proline–glutamic acid–serine–threonine; ZF: zinc finger.