Selective Enhancer Dependencies in MYC-Intact and MYC-Rearranged Germinal Center B-cell Diffuse Large B-cell Lymphoma.

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.

ETV6 Deficiency Unlocks ERG-Dependent Microsatellite Enhancers to Drive Aberrant Gene Activation in B-Lymphoblastic Leukemia.

Unlabelled: Distal enhancers play critical roles in sustaining oncogenic gene-expression programs. We identify aberrant enhancer-like activation of GGAA tandem repeats as a characteristic feature of B-cell acute lymphoblastic leukemia (B-ALL) with genetic defects of the ETV6 transcriptional repressor, including ETV6-RUNX1+ and ETV6-null B-ALL. We show that GGAA repeat enhancers are direct activators of previously identified ETV6-RUNX1+/- like B-ALL "signature" genes, including the likely leukemogenic driver EPOR.