{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE343nnn/GSE343852/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":[" Genome binding/occupancy profiling by high throughput sequencing","Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE343852"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Ezh2-Y641F mutations are distinct from EZH2 overexpression and impact germinal center B cells in a timing-dependent manner","description":"Germinal center (GC) B cell-derived Non-Hodgkin Lymphomas (NHL) frequently exhibit gain-of-function alterations in the H3K27 methyltransferase EZH2, including a heterozygous, somatic hotspot mutation at position Y646 (Y641 in mice) or overexpression of wild-type protein (EZH2OE). To determine whether Ezh2Y646 mutations and EZH2OE are functionally equivalent or distinct gain-of-function events in GC B cells, we directly compared EZH2Y641F/+ and EZH2OE using conditional mouse models that activate these events either throughout the B lineage or specifically within GC B cells. Across transplant and non-transplant settings, we found that EZH2OE yields surprisingly weak phenotypes, while EZH2Y641F/+ causes strong but timing-dependent effects in GC cells. We observed that GC-specific EZH2Y641F/+ causes GC expansion and promotes lymphoma phenotypes, whereas early B lineage activation reduced GC fitness. Furthermore, transcriptional analysis and H3K27me3 profiling revealed that EZH2OE and EZH2Y641F/+ are non-equivalent molecular events. EZH2OE minimally impacted gene expression and H3K27me3 profiles compared to controls, while EZH2Y641F/+ caused widespread differential gene expression and broad redistribution of H3K27me3. The extent and localization of the redistribution depend on when the mutation is activated in the B lineage, potentially explaining why early vs. GC-restricted EZH2Y641F produce disparate GC phenotypes. Ultimately, we determined that EZH2Y641F/+ and EZH2OE are functionally distinct events, with only GC-restricted EZH2Y641F/+ contributing to GC B cell transformation phenotypes. Our evidence supports the conclusion that EZH2Y641F/+ is a neomorph of EZH2WT rather than a pure gain-of-function event and reveals the context-dependent nature of its role in B-NHL.","dates":{"publication":"2026/09/10"},"accession":"GSE343852","cross_references":{"GSM":["GSM10043094","GSM10043095","GSM10043096","GSM10043097","GSM10043090","GSM10043091","GSM10043092","GSM10043093","GSM9963661","GSM9963660","GSM10043087","GSM9963663","GSM9963662","GSM10043088","GSM9963665","GSM10043089","GSM9963664","GSM9963667","GSM9963666","GSM9963669","GSM9963668","GSM10043083","GSM10043084","GSM10043085","GSM10043086","GSM10043080","GSM10043081","GSM10043082","GSM9963650","GSM9963652","GSM10043076","GSM10043110","GSM9963651","GSM10043077","GSM10043078","GSM9963654","GSM10043111","GSM9963653","GSM10043079","GSM9963656","GSM9963655","GSM9963658","GSM9963657","GSM9963659","GSM10043102","GSM9963681","GSM9963680","GSM10043103","GSM10043104","GSM9963683","GSM9963682","GSM10043105","GSM9963641","GSM9963640","GSM9963643","GSM10043100","GSM9963642","GSM10043101","GSM9963645","GSM9963644","GSM9963647","GSM9963646","GSM10043106","GSM9963649","GSM10043107","GSM9963648","GSM10043108","GSM10043109","GSM9963670","GSM9963672","GSM9963671","GSM10043098","GSM9963674","GSM9963673","GSM10043099","GSM9963676","GSM9963675","GSM9963678","GSM9963677","GSM9963636","GSM9963679","GSM9963638","GSM9963637","GSM9963639"],"GPL":["34290"],"GSE":["343852"],"taxon":["Mus musculus"]}}