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

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 enh...

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Bibliographic Details
Published in:Cancer discovery 2015-10, Vol.5 (10), p.1058-1071
Main Authors: Ryan, Russell J H, Drier, Yotam, Whitton, Holly, Cotton, M Joel, Kaur, Jasleen, Issner, Robbyn, Gillespie, Shawn, Epstein, Charles B, Nardi, Valentina, Sohani, Aliyah R, Hochberg, Ephraim P, Bernstein, Bradley E
Format: Article
Language:English
Subjects:
Acetylation
Cell Line, Tumor
Chromatin Immunoprecipitation
Chromosomes, Human, Pair 3
Chromosomes, Human, Pair 8
DNA-Binding Proteins - genetics
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 - metabolism
Humans
Lymphoma, B-Cell - diagnosis
Lymphoma, B-Cell - genetics
Lymphoma, B-Cell - metabolism
Lymphoma, Mantle-Cell - diagnosis
Lymphoma, Mantle-Cell - genetics
MEF2 Transcription Factors - metabolism
Oncogenes
p300-CBP Transcription Factors - metabolism
Polymorphism, Genetic
Protein Binding
Proto-Oncogene Proteins c-bcl-6
Recombination, Genetic
Translocation, Genetic
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Summary: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. 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.
ISSN:2159-8274
2159-8290
DOI:10.1158/2159-8290.cd-15-0370