title: Detection of Enhancer-Associated Rearrangements Reveals Mechanisms of Oncogene Dysregulation in B-cell Lymphoma.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Broad Institute of Harvard University and MIT, Cambridge, Massachusetts.
authors.forename: Russell J H
authors.initials: RJ
authors.lastname: Ryan
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Broad Institute of Harvard University and MIT, Cambridge, Massachusetts.
authors.forename: Yotam
authors.initials: Y
authors.lastname: Drier
authors.affiliation: Broad Institute of Harvard University and MIT, Cambridge, Massachusetts.
authors.forename: Holly
authors.initials: H
authors.lastname: Whitton
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Broad Institute of Harvard University and MIT, Cambridge, Massachusetts.
authors.forename: M Joel
authors.initials: MJ
authors.lastname: Cotton
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Broad Institute of Harvard University and MIT, Cambridge, Massachusetts.
authors.forename: Jasleen
authors.initials: J
authors.lastname: Kaur
authors.affiliation: Broad Institute of Harvard University and MIT, Cambridge, Massachusetts.
authors.forename: Robbyn
authors.initials: R
authors.lastname: Issner
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Broad Institute of Harvard University and MIT, Cambridge, Massachusetts.
authors.forename: Shawn
authors.initials: S
authors.lastname: Gillespie
authors.affiliation: Broad Institute of Harvard University and MIT, Cambridge, Massachusetts.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Epstein
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Valentina
authors.initials: V
authors.lastname: Nardi
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Aliyah R
authors.initials: AR
authors.lastname: Sohani
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Ephraim P
authors.initials: EP
authors.lastname: Hochberg
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Broad Institute of Harvard University and MIT, Cambridge, Massachusetts. Bernstein.Bradley@mgh.harvard.edu.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D002893:Chromosomes, Human, Pair 3; D002898:Chromosomes, Human, Pair 8; D004268:DNA-Binding Proteins / Q000235:genetics; D004742:Enhancer Elements, Genetic; D020440:Gene Duplication; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D016259:Genes, myc; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D016393:Lymphoma, B-Cell / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D020522:Lymphoma, Mantle-Cell / Q000175:diagnosis / Q000235:genetics; D064326:MEF2 Transcription Factors / Q000378:metabolism; D009857:Oncogenes; D011110:Polymorphism, Genetic; D011485:Protein Binding; D051560:Proto-Oncogene Proteins c-bcl-6; D011995:Recombination, Genetic; D014178:Translocation, Genetic; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D006657:Histones; D064326:MEF2 Transcription Factors; D051560:Proto-Oncogene Proteins c-bcl-6; D050880:p300-CBP Transcription Factors