Detection of enhancer-associated rearrangements reveals mechanisms of oncogene dysregulation in B-cell lymphoma

Russell J.H. Ryan, Yotam Drier, Holly Whitton, M. Joel Cotton, Jasleen Kaur, Robbyn Issner, Shawn Gillespie, Charles B. Epstein, Valentina Nardi, Aliyah R. Sohani, Ephraim P. Hochberg, Bradley E. Bernstein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

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 PEARChIP, 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.

Original languageAmerican English
Pages (from-to)1058-1071
Number of pages14
JournalCancer Discovery
Volume5
Issue number10
DOIs
StatePublished - Oct 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015 American Association for Cancer Research.

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