Enhancer Sequence Variants and Transcription-Factor Deregulation Synergize to Construct Pathogenic Regulatory Circuits in B-Cell Lymphoma

• Published in: Immunity (Cambridge, Mass.) Mass.), 2015-01, Vol.42 (1), p.186-198
• Main Authors: Koues, Olivia I., Kowalewski, Rodney A., Chang, Li-Wei, Pyfrom, Sarah C., Schmidt, Jennifer A., Luo, Hong, Sandoval, Luis E., Hughes, Tyler B., Bednarski, Jeffrey J., Cashen, Amanda F., Payton, Jacqueline E., Oltz, Eugene M.
• Format: Article
• Language: English
• Subjects: Adult; Aged; B-Lymphocytes - physiology; Biopsy; Cancer; Cell Transformation, Neoplastic; Deoxyribonucleic acid; DNA; Epigenesis, Genetic; Epigenetics; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genomes; Germinal Center - pathology; Humans; Immune system; Lymphocyte Activation - genetics; Lymphoma; Lymphoma, B-Cell - genetics; Male; Middle Aged; Mutation; Mutation - genetics; Regulatory Elements, Transcriptional - genetics; Regulatory Elements, Transcriptional - immunology; Transcription Factors - metabolism
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2014.12.021

Most B-cell lymphomas arise in the germinal center (GC), where humoral immune responses evolve from potentially oncogenic cycles of mutation, proliferation, and clonal selection. Although lymphoma gene expression diverges significantly from GC B cells, underlying mechanisms that alter the activities of corresponding regulatory elements (REs) remain elusive. Here we define the complete pathogenic circuitry of human follicular lymphoma (FL), which activates or decommissions REs from normal GC B cells and commandeers enhancers from other lineages. Moreover, independent sets of transcription factors, whose expression was deregulated in FL, targeted commandeered versus decommissioned REs. Our approach revealed two distinct subtypes of low-grade FL, whose pathogenic circuitries resembled GC B or activated B cells. FL-altered enhancers also were enriched for sequence variants, including somatic mutations, which disrupt transcription-factor binding and expression of circuit-linked genes. Thus, the pathogenic regulatory circuitry of FL reveals distinct genetic and epigenetic etiologies for GC B-cell transformation. [Display omitted] •Complete gene-regulatory circuits for human B-cell lymphoma and normal GC B subsets•Two cohorts of transcription factors target pirated versus lost enhancers in lymphoma•Pathogenic enhancers enriched for SNPs and somatic mutations affect factor binding•Epigenome-centric analysis identifies two new subtypes of follicular lymphoma A fundamental focus of lymphoma biology remains the identification of cooperative mechanisms that promote oncogenesis. Oltz and colleagues define the pathogenic circuitry of human follicular lymphoma (FL), revealing distinct genetic and epigenetic etiologies for germinal-center B-cell transformation.