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Detection of Enhancer-Associated Rearrangements Reveals Mechanisms of Oncogene Dysregulation in B-cell Lymphoma [ChIP-Seq]

ABSTRACT: B-cell lymphomas frequently demonstrate inter-chromosomal translocations that lead to oncogene activation by heterologous distal regulatory elements. We utilized a novel approach, termed ‘Pinpointing of Enhancer-Associated Rearrangements by Chromatin Immunoprecipitation’ or PEAR-ChIP, to simultaneously map enhancer activity and proximal rearrangements in lymphoma cell lines and patient biopsies. The method efficiently detects rearrangements within and adjacent to known cancer genes such as CCND1, BCL2, MYC, PDCD1LG2, NOTCH1, CIITA, and SGK1, as well as novel enhancer duplication events of likely oncogenic significance. We identify novel enhancer-like elements in the MYC locus that interact with the MYC promoter, are associated with germline polymorphisms that alter lymphoma risk, show lymphoma subtype-specific acetylation, and are silenced in lymphomas where MYC is activated by “enhancer hijacking” translocations. We also identify an array of BCL6-interacting enhancers that are subject to genomic alterations, are acetylated by the BCL6-activating transcription factor MEF2B, and target the MYC promoter in the context of a “pseudo-double-hit” t(3;8) genomic rearrangement linking the BCL6 and MYC loci. Our findings uncover diverse mechanisms by which genomic rearrangements can lead to aberrations in enhancer-mediated oncogene regulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE69558 | GEO | 2015/08/04

SECONDARY ACCESSION(S): PRJNA285847

REPOSITORIES: GEO

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Project description:MYC translocations are the biologic hallmark of Burkitt lymphomas but also occur in other mature B-cell lymphomas. If accompanied by chromosomal breaks targeting the BCL2 and/or BCL6 oncogenes, these MYC translocation-positive (MYC+) lymphomas are called double-hit lymphomas (DHLs); otherwise, the term single-hit lymphoma (SHL) is applied. In order to characterize the biologic features of these MYC+ lymphomas other than Burkitt lymphomas, we explored, after exclusion of molecular Burkitt lymphoma (mBL) as defined by gene expression profiling (GEP), the molecular, pathological and clinical aspects of 80 MYC translocation (MYC+) lymphomas (31 SHL, 26 BCL2+/MYC+, 14 BCL6+/MYC+, 6 BCL2+/BCL6+/MYC+ and 3 MYC+ lymphomas with unknown BCL6 status). Comparison of SHL and DHL revealed no difference in frequency of MYC partner (IG/non-IG), genomic complexity or MYC expression and no differences in GEP. DHL showed a more frequent GCB-like GEP and higher IGH and MYC mutation rates. GEP revealed 130 differentially expressed genes between BCL6+/MYC+ and BCL2+/MYC+ DHL. BCL2+/MYC+ DHL showed a more frequent GCB-like GEP. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In contrast to mBL and lymphomas without MYC break, SHL and DHL patients had similar poor outcome. Our data suggest that after excluding mBL, MYC+ lymphomas could be biologically widely lumped without further need for subclassification. 32 diffuse large B-cell lymphoma samples were hybridized to HG-U133A Affymetrix GeneChips. In addition, this study contains 30 already published samples, which contribute to GSE4475 (Hummel et al. 2006 (PMID 16760442)), as well as 18 already published samples from GSE22470 (Salaverria et al. 2011 (PMID 21487109)). No re-normalisation of the published samples was performed. The complete dataset representing: (1) the 32 diffuse large B-cell lymphoma Samples, (2) the 30 Samples from GSE4475 and (3) the 18 Samples from GSE22470, is linked below as a supplementary file

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Detection of Enhancer-Associated Rearrangements Reveals Mechanisms of Oncogene Dysregulation in B-cell Lymphoma [ChIP-Seq]

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