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.