Roles of BCL6 in normal and transformed germinal center B cells

Abstract

Summary: BCL6 is a transcriptional repressor required in mature B cells during the germinal center (GC) reaction. Multiple mechanisms act coordinately to timely modulate BCL6 expression at transcriptional and post‐transcriptional levels. BCL6 prevents premature activation and differentiation of GC B cells and provides an environment tolerant of the DNA breaks associated with immunoglobulin gene remodeling mechanisms involved in the production of high‐affinity antibodies of different isotypes. The critical functions exerted by BCL6 during normal B‐cell development can be hijacked by the malignant transformation process. Indeed, BCL6 is targeted by genetic aberrations and acts as an oncogene in GC‐derived lymphomas. The aberrations affecting BCL6 interfere with the multiple levels of regulation that grant a fine tuning of BCL6 expression and activity in physiologic conditions. This review summarizes the current knowledge on BCL6 function and its role in lymphomagenesis.

Inhibition of ZEB1 by miR-200 characterizes Helicobacter pylori-positive gastric diffuse large B-cell lymphoma with a less aggressive behavior

“…The germinal center B-cell type has a better prognosis than the activated B-cell type. 27 As BCL6 is the master transcription factor for germinal center B cells, 28 the association of higher expression of BCL6 with a better prognosis in gastric diffuse large B-cell lymphomas is consistent with the finding that nodal diffuse large B-cell lymphomas of the germinal center B-cell type have a better prognosis. 4,27 However, BCL6 may contribute to a better prognosis through additional pathways other than promoting germinal center B-cell differentiation.…”

Mechanisms of action of BCL6 during germinal center B cell development

“…BCL6 mediates these effects by directly repressing DNA damage sensing and checkpoint genes such as DNA damage sensor ATR (ataxia telangiectasia and Rad3 related), TP53 (tumor protein p53) tumor suppressor and cell cycle arrest gene CDKN1A (cyclin-dependent kinase inhibitor 1A) [27][28][29]. In addition, BCL6 blocks premature activation by T cells or other soluble signals through inhibiting a number of pathways involved in B-cell activation in T-cell dependent immune [11][12][13]. This function of BCL6 may be important to prevent centroblasts to exit from the GC before they complete the phase of proliferative expansion and of antibody affinity maturation.…”

“…Deregulated BCL6 expression, due to chromosomal translocation or mutations of its own promoter, or genetic alterations in pathways normally regulated by BCL6, is commonly associated with DLBCLs and less frequently associated with FLs [11,33,34]. The pro-survival and proliferation functions of BCL6 appear to make GC B cells prone to malignant transformation.…”

“…Loss of BCL6 in each cell type results in abrogation of the GC reaction. BCL6 acts as an oncogene in GC-derived B-cell lymphoma, which is usually characterized by deregulated BCL6 expression due to chromosomal translocation or mutations of its promoter, or feature genetic lesions in pathways normally regulated by BCL6 [11,12]. From the biochemical mechanism standpoint, BCL6 exerts its effects mostly through recruitment of various co-repressor complexes [13].…”

IL-21 acts as a promising therapeutic target in systemic lupus erythematosus by regulating plasma cell differentiation

“…At the end of the GC reaction, Bcl-6 expression is downregulated and Blimp-1 expression is upregulated to facilitate the differentiation into long-lived PCs. 74 When the balance favors PC differentiation, Blimp-1 is derepressed from Bcl-6 and suppresses PAX-5; this leads to the XBP-1 de-repression, which promotes PC differentiation. Bcl-6 and PAX-5 promote B-cell proliferation and the GC reaction by repressing Blimp-1 and XBP-1 (Figure 3b).…”