{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:10:00Z","timestamp":1790784600268,"version":"4.1.0"},"posted":{"date-parts":[[2023,5,3]]},"group-title":"Cancer Biology","reference-count":57,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,5,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  High expression of\n                  <jats:italic>MYC<\/jats:italic>\n                  and its target genes define a subset of germinal center B-cell diffuse large B-cell lymphoma (GCB-DLBCL) associated with poor outcomes. Half of these high-grade cases show chromosomal rearrangements between the\n                  <jats:italic>MYC<\/jats:italic>\n                  locus and heterologous enhancer-bearing loci, while focal deletions of the adjacent non-coding gene\n                  <jats:italic>PVT1<\/jats:italic>\n                  are enriched in\n                  <jats:italic>MYC<\/jats:italic>\n                  -intact cases. To identify genomic drivers of\n                  <jats:italic>MYC<\/jats:italic>\n                  activation, we used high-throughput CRISPR-interference (CRISPRi) profiling of candidate enhancers in the\n                  <jats:italic>MYC<\/jats:italic>\n                  locus and rearrangement partner loci in GCB-DLBCL cell lines and mantle cell lymphoma (MCL) comparators that lacked common rearrangements between\n                  <jats:italic>MYC<\/jats:italic>\n                  and immunoglobulin (Ig) loci. Rearrangements between\n                  <jats:italic>MYC<\/jats:italic>\n                  and non-Ig loci were associated with unique dependencies on specific enhancer subunits within those partner loci. Notably, fitness dependency on enhancer modules within the\n                  <jats:italic>BCL6<\/jats:italic>\n                  super-enhancer (\n                  <jats:italic>BCL6<\/jats:italic>\n                  -SE) cluster regulated by a transcription factor complex of MEF2B, POU2F2, and POU2AF1 was higher in cell lines bearing a recurrent\n                  <jats:italic>MYC::BCL6<\/jats:italic>\n                  -SE rearrangement. In contrast, GCB-DLBCL cell lines without\n                  <jats:italic>MYC<\/jats:italic>\n                  rearrangement were highly dependent on a previously uncharacterized 3\u2019 enhancer within the\n                  <jats:italic>MYC<\/jats:italic>\n                  locus itself (GCBME-1), that is regulated in part by the same triad of factors. GCBME-1 is evolutionarily conserved and active in normal germinal center B cells in humans and mice, suggesting a key role in normal germinal center B cell biology. Finally, we show that the\n                  <jats:italic>PVT1<\/jats:italic>\n                  promoter limits\n                  <jats:italic>MYC<\/jats:italic>\n                  activation by either native or heterologous enhancers and demonstrate that this limitation is bypassed by 3\u2019 rearrangements that remove\n                  <jats:italic>PVT1<\/jats:italic>\n                  from its position in\n                  <jats:italic>cis<\/jats:italic>\n                  with the rearranged\n                  <jats:italic>MYC<\/jats:italic>\n                  gene.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Key points<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>\n                        CRISPR-interference screens identify a conserved germinal center B cell\n                        <jats:italic>MYC<\/jats:italic>\n                        enhancer that is essential for GCB-DLBCL lacking\n                        <jats:italic>MYC<\/jats:italic>\n                        rearrangements.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Functional profiling of\n                        <jats:italic>MYC<\/jats:italic>\n                        partner loci reveals principles of\n                        <jats:italic>MYC<\/jats:italic>\n                        enhancer-hijacking activation by non-immunoglobulin rearrangements.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2023.05.02.538892","type":"posted-content","created":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T11:15:20Z","timestamp":1683112520000},"source":"Crossref","is-referenced-by-count":4,"title":["Selective Enhancer Dependencies in\n     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