Abstract
B cell lymphoma is a clinically heterogeneous and pathologically diverse group of diseases with a strong epigenetic component. The B cell lymphoma 6 (BCL6) gene encodes a transcription factor that is critical for normal germinal center reaction B cell development by maintaining an epigenetic and transcriptional state that is permissive for cellular proliferation and DNA damage. The activity of BCL6 can be deregulated by a variety of mechanisms and contributes to the development of B-cell lymphoma. Here we review the direct and indirect mechanisms BCL6 dysregulation in B cell lymphoma, including transcriptional and post-translational regulation of BCL6 expression and activity, and the perturbation of BCL6-regulated epigenetic programs by cooperating chromatin modifying gene mutations. We underscore the critical importance of BCL6 and its associated epigenetic programs in the development of B-cell lymphoma, and discuss avenues for the therapeutic targeting of BCL6 in this context.
Highlights
Epigenetic alterations control gene transcription through DNA methylation and the posttranslational modification of chromatin, which leads to the activation or silencing of genes
Deregulation of B cell lymphoma 6 (BCL6) in Lymphoma three conserved domains that are important for its function; the N-terminal BTB/POZ domain that recruits corepressors such as BCOR, NCOR1, and NCOR2, a central RD2 region that interacts with CTBP, NuRD, MTA2, and HDAC2, and a C-terminal zinc finger domain that interacts with specific DNA sequence (Chang et al, 1996; Ahmad et al, 2003; Ghetu et al, 2008; Huang et al, 2014)
The CREBBP and EP300 genes are recurrently mutated in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), which may result in the reduced acetylation of BCL6 and associated increases in BCL6 activity (Pasqualucci et al, 2011a)
Summary
Epigenetic alterations control gene transcription through DNA methylation and the posttranslational modification of chromatin, which leads to the activation or silencing of genes. The BCL6 gene is the master regulator of GCB cell development and functions via the recruitment of co-repressor complexes that catalyze broad epigenetic changes.
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