GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE327nnn/GSE327307/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE327307GEOGSEfalseDOT1L shapes ncPRC1-target gene repression to maintain cell identity of DLBCL [RNA-Seq]Germinal center (GC) B cell-like diffuse large B cell lymphoma (GCB-DLBCL) depends on the cooperative activity of the histone methyltransferases DOT1L and EZH2 to maintain its pro-proliferative GCB cell identity while repressing plasma cell (PC) differentiation. To explore the mechanisms underlying the co-dependency between DOT1L and EZH2 in GCB-DLBCL, we performed an EZH2 inhibition (EZH2i)-anchored genome-wide CRISPR interference screen and identified multiple candidate genes encoding components of non-canonical (nc) PRC1 complexes, including USP7, KDM2B, RING1, and PCGF1. We identified USP7 as potential direct target of DOT1L, whose downregulation was associated with increased EZH2i sensitivity in multiple GCB-DLBCL cell lines. Furthermore, we observed that DOT1L influences the composition of chromatin-bound ncPRC1 complexes and regulates, in part, the deposition of H2AK119 monoubiquitination (H2AK119ub1) at gene promoters co-occupied by H3K27me3, here defined as PRC1/2 target genes. These PRC1/2 targets were specifically enriched in PC signature genes, whose derepression was associated with DOT1L inhibition (DOT1Li)-mediated loss of H2AK119ub1. This study reveals novel insights into the role of DOT1L and its functional co-dependence with EZH2 in maintaining GCB identity in DLBCL, supporting a model in which concurrent reduction of H2AK119ub1 and H3K27me3 promotes differentiation toward an anti-proliferative, plasma cell–like state.2026/06/19GSE327307GSM9653220GSM9653221GSM9653210GSM9653211GSM9653222GSM9653223GSM9653212GSM9653217GSM9653206GSM9653218GSM9653207GSM9653208GSM9653219GSM9653209GSM9653224GSM9653213GSM9653214GSM9653203GSM9653225GSM9653226GSM9653215GSM9653204GSM9653205GSM965321624676327307Homo sapiens