title: Enhancer sequence variants and transcription-factor deregulation synergize to construct pathogenic regulatory circuits in B-cell lymphoma.
abstract: 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.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Olivia I
authors.initials: OI
authors.lastname: Koues
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Kowalewski
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Chang
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Pyfrom
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Schmidt
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Luo
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Sandoval
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Tyler B
authors.initials: TB
authors.lastname: Hughes
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Bednarski
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Amanda F
authors.initials: AF
authors.lastname: Cashen
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: jpayton@wustl.edu.
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Payton
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: eoltz@wustl.edu.
authors.forename: Eugene M
authors.initials: EM
authors.lastname: Oltz
mesh_terms: D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D018858:Germinal Center / Q000473:pathology*; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D050436:Regulatory Elements, Transcriptional / Q000235:genetics / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors