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Cancer Discov DOI:10.1158/2159-8290.CD-15-0370

Detection of Enhancer-Associated Rearrangements Reveals Mechanisms of Oncogene Dysregulation in B-cell Lymphoma.

Publication TypeJournal Article
Year of Publication2015
AuthorsRyan, RJH, Drier, Y, Whitton, H, M Cotton, J, Kaur, J, Issner, R, Gillespie, S, Epstein, CB, Nardi, V, Sohani, AR, Hochberg, EP, Bernstein, BE
JournalCancer Discov
Volume5
Issue10
Pages1058-71
Date Published2015 Oct
ISSN2159-8290
KeywordsAcetylation, Cell Line, Tumor, Chromatin Immunoprecipitation, Chromosomes, Human, Pair 3, Chromosomes, Human, Pair 8, DNA-Binding Proteins, Enhancer Elements, Genetic, Gene Duplication, Gene Expression Regulation, Neoplastic, Gene Rearrangement, Genes, myc, Genetic Predisposition to Disease, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Histones, Humans, Lymphoma, B-Cell, Lymphoma, Mantle-Cell, MEF2 Transcription Factors, Oncogenes, p300-CBP Transcription Factors, Polymorphism, Genetic, Protein Binding, Recombination, Genetic, Translocation, Genetic
Abstract

UNLABELLED: B-cell lymphomas frequently contain genomic rearrangements that lead to oncogene activation by heterologous distal regulatory elements. We used a novel approach called "pinpointing enhancer-associated rearrangements by chromatin immunoprecipitation," or PEAR-ChIP, to simultaneously map enhancer activity and proximal rearrangements in lymphoma cell lines and patient biopsies. This method detects rearrangements involving known cancer genes, including CCND1, BCL2, MYC, PDCD1LG2, NOTCH1, CIITA, and SGK1, as well as novel enhancer duplication events of likely oncogenic significance. We identify lymphoma subtype-specific enhancers in the MYC locus that are silenced in lymphomas with MYC-activating rearrangements and are associated with germline polymorphisms that alter lymphoma risk. We show that BCL6-locus enhancers are acetylated by the BCL6-activating transcription factor MEF2B, and can undergo genomic duplication, or target the MYC promoter for activation in the context of a "pseudo-double-hit" t(3;8)(q27;q24) rearrangement linking the BCL6 and MYC loci. Our work provides novel insights regarding enhancer-driven oncogene activation in lymphoma.

SIGNIFICANCE: We demonstrate a novel approach for simultaneous detection of genomic rearrangements and enhancer activity in tumor biopsies. We identify novel mechanisms of enhancer-driven regulation of the oncogenes MYC and BCL6, and show that the BCL6 locus can serve as an enhancer donor in an "enhancer hijacking" translocation.

DOI10.1158/2159-8290.CD-15-0370
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/26229090?dopt=Abstract

Alternate JournalCancer Discov
PubMed ID26229090
PubMed Central IDPMC4592453
Grant ListT32CA009216 / CA / NCI NIH HHS / United States
T32GM007748 / GM / NIGMS NIH HHS / United States
U54 HG004570 / HG / NHGRI NIH HHS / United States