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

Abstract

<div>Abstract<p>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 <i>CCND1</i>, <i>BCL2</i>, <i>MYC</i>, <i>PDCD1LG2</i>, <i>NOTCH1</i>, <i>CIITA</i>, and <i>SGK1</i>, as well as novel enhancer duplication events of likely oncogenic significance. We identify lymphoma subtype–specific enhancers in the <i>MYC</i> locus that are silenced in lymphomas with <i>MYC</i>-activating rearrangements and are associated with germline polymorphisms that alter lymphoma risk. We show that <i>BCL6</i>-locus enhancers are acetylated by the <i>BCL6</i>-activating transcription factor MEF2B, and can undergo genomic duplication, or target the <i>MYC</i> promoter for activation in the context of a “pseudo-double-hit” t(3;8)(q27;q24) rearrangement linking the <i>BCL6</i> and <i>MYC</i> loci. Our work provides novel insights regarding enhancer-driven oncogene activation in lymphoma.</p><p><b>Significance:</b> 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 <i>MYC</i> and <i>BCL6</i>, and show that the <i>BCL6</i> locus can serve as an enhancer donor in an “enhancer hijacking” translocation. <i>Cancer Discov; 5(10); 1058–71. ©2015 AACR</i>.</p><p><i>See related commentary by Mack et al., p. 1018</i>.</p><p>This article is highlighted in the In This Issue feature, p. 1005</p></div>