TY - JOUR
T1 - Enhancer Sequence Variants and Transcription-Factor Deregulation Synergize to Construct Pathogenic Regulatory Circuits in B-Cell Lymphoma
AU - Koues, Olivia I.
AU - Kowalewski, Rodney A.
AU - Chang, Li Wei
AU - Pyfrom, Sarah C.
AU - Schmidt, Jennifer A.
AU - Luo, Hong
AU - Sandoval, Luis E.
AU - Hughes, Tyler B.
AU - Bednarski, Jeffrey J.
AU - Cashen, Amanda F.
AU - Payton, Jacqueline E.
AU - Oltz, Eugene M.
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/1/20
Y1 - 2015/1/20
N2 - 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 Bcells and commandeers enhancers from other lineages. Moreover, independent sets of transcription factors, whose expression was deregulated inFL, 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-factorbinding and expression of circuit-linked genes. Thus, the pathogenic regulatory circuitry of FL reveals distinct genetic and epigenetic etiologies for GC B-cell transformation.
AB - 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 Bcells and commandeers enhancers from other lineages. Moreover, independent sets of transcription factors, whose expression was deregulated inFL, 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-factorbinding and expression of circuit-linked genes. Thus, the pathogenic regulatory circuitry of FL reveals distinct genetic and epigenetic etiologies for GC B-cell transformation.
UR - http://www.scopus.com/inward/record.url?scp=84921320758&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2014.12.021
DO - 10.1016/j.immuni.2014.12.021
M3 - Article
C2 - 25607463
AN - SCOPUS:84921320758
SN - 1074-7613
VL - 42
SP - 186
EP - 198
JO - Immunity
JF - Immunity
IS - 1
ER -