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 are dependent on an evolutionarily-conserved enhancer we name “germinal center MYC enhancer 1” (GME-1), which is activated by the transcription factor complex of OCT2, OCA-B, and MEF2B, shows an active chromatin state in normal human and mouse germinal center B cells, and demonstrates selective acetylation and MYC promoter topological interactions in MYC-intact GCB-DLBCL biopsies. Whole-genome sequencing identified tandem copy gains of the GME-1 enhancer 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.

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Supplementary data

Supplementary Table S1

Experimental resources: Oligonucleotide sequences, cell line information, and whole genome sequencing data sources

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Supplementary Table S2

Analysis of NFR and gene–focused CRISPRi screens in 8 lymphoma cell lines.

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Supplementary Table S3

Significant peaks of sgRNA enrichment or depletion identified in sliding-window analysis of MYC locus tiling CRISPRi screens

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Supplementary Table S4

Demographic and clinical diagnostic information about DLBCL patient biopsies used for Hi-C and H3K27ac ChIP-Seq

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Supplementary Figures and Legends

Supplementary figures S1-S7, showing additional information relevant to the corresponding main figure.

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