Abstract
High expression of MYC and its target genes identify germinal center B-cell diffuse large B-cell lymphomas (GCB-DLBCL) associated with poor outcomes. We used CRISPR-interference profiling of human lymphoma cell lines to define essential enhancers in the MYC locus and non-immunoglobulin rearrangement partner loci, including a recurrent rearrangement between MYC and the BCL6 locus control region. GCB-DLBCL cell lines without MYC rearrangement were dependent on an evolutionarily conserved enhancer we name “GC B cell MYC enhancer 1,” which was found to be activated by the transcription factor complex of OCT2, OCA-B, and MEF2B, showed an active chromatin state in normal human and mouse GC B cells, and demonstrated selective acetylation and MYC promoter topological interactions in MYC-intact GCB-DLBCL biopsies. Whole-genome sequencing identified tandem copy gains of GC MYC enhancer 1 as a rare but recurrent event in DLBCL. Our findings shed new light on mechanisms that dysregulate MYC, a key driver of B-cell malignancy.
Aberrant MYC activity defines the most aggressive GCB-DLBCLs. We characterized a mechanism of MYC transcriptional activation via a native enhancer that is active in MYC-intact GCB-DLBCL, establishing fitness-sustaining cis- and trans-regulatory circuitry in GCB-DLBCL models that lack MYC enhancer-hijacking rearrangement.
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