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Immunity. 2015 Jan 20;42(1):186-98. doi: 10.1016/j.immuni.2014.12.021. Epub 2014 Dec 25.

Enhancer sequence variants and transcription-factor deregulation synergize to construct pathogenic regulatory circuits in B-cell lymphoma.

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
2
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
3
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
4
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: jpayton@wustl.edu.
5
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: eoltz@wustl.edu.

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.

PMID:
25607463
PMCID:
PMC4302272
DOI:
10.1016/j.immuni.2014.12.021
[Indexed for MEDLINE]
Free PMC Article
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