Pathogenic variations driving malignant follicular lymphoma regulatory circuitry (LB489)

Abstract

Regulatory elements play a major role in establishing cell‐specific gene expression patterns. Perturbations in these non‐coding DNA regions (e.g., promoters and enhancers) facilitate gene expression changes associated with lymphomagenesis. To investigate the regulatory circuitry driving follicular lymphoma (FL), a germinal center‐derived B cell lymphoma, we generated global chromatin maps of histone modifications associated with active REs in primary FL tumors and normal human B cells. Comparative epigenomic analyses produced a collection of enhancers that are dysregulated during lymphomagenesis. We then identified sequence motifs that are enriched significantly in the augmented regulatory elements (REs) from ten FL samples. The most recurrent and significant motifs bind families of factors known to be important for transcriptional regulation in lymphocytes, including SPI, BCL6, KLF, POU, and TCF. Subsequent informatics analyses revealed transcription factor (TF) binding motifs within a subset of enhancers that were altered by single nucleotide variants (SNVs), suggesting a functional role for intergenic SNVs in tumor pathogenesis. Because changes to the epigenome are reversible, improved understanding of these pathogenic regulatory circuits will provide attractive therapeutic targets to reverse malignant gene expression. Data from our approach are expected to facilitate early NHL diagnosis, enhance prognostic schemes, and identify novel therapeutic targets.Grant Funding Source: Supported by NIH grant CA156690