{"doi":"10.1101/2023.02.13.528351","title":"Cooperative super-enhancer inactivation caused by heterozygous loss of CREBBP and KMT2D skews B cell fate decisions and yields T cell-depleted lymphomas","abstract":"ABSTRACT Mutations affecting enhancer chromatin regulators CREBBP and KMT2D are highly co-occurrent in germinal center (GC)-derived lymphomas and other tumors, even though regulating similar pathways. Herein, we report that combined haploinsufficiency of Crebbp and Kmt2d (C+K) indeed accelerated lymphomagenesis. C+K haploinsufficiency induced GC hyperplasia by altering cell fate decisions, skewing B cells away from memory and plasma cell differentiation. C+K deficiency particularly impaired enhancer activation for immune synapse genes involved in exiting the GC reaction. This effect was especially severe at super-enhancers for immunoregulatory and differentiation genes. Mechanistically, CREBBP and KMT2D formed a complex, were highly co-localized on chromatin, and were required for each-other’s stable recruitment to enhancers. Notably, C+K lymphomas in mice and humans manifested significantly reduced CD8 + T-cell abundance. Hence, deficiency of C+K cooperatively induced an immune evasive phenotype due at least in part to failure to activate key immune synapse super-enhancers, associated with altered immune cell fate decisions. SIGNIFICANCE Although CREBBP and KMT2D have similar enhancer regulatory functions, they are paradoxically co-mutated in lymphomas. We show that their combined loss causes specific disruption of super-enhancers driving immune synapse genes. Importantly, this leads to reduction of CD8 cells in lymphomas, linking super-enhancer function to immune surveillance, with implications for immunotherapy resistance.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":392189,"datarank":0.26876392038420827,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.0,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":237408,"name":"Christopher R. Chin","orcid":"0000-0002-2140-3197","position":1,"is_corresponding":false},{"id":257241,"name":"Hsia‐Yuan Ying","orcid":null,"position":2,"is_corresponding":false},{"id":227777,"name":"Cem Meydan","orcid":"0000-0002-0663-6216","position":3,"is_corresponding":false},{"id":352111,"name":"Matthew Teater","orcid":null,"position":4,"is_corresponding":false},{"id":903158,"name":"Min Xia","orcid":"0000-0002-1093-5008","position":5,"is_corresponding":false},{"id":296270,"name":"Pedro Farinha","orcid":"0000-0001-9364-9391","position":6,"is_corresponding":false},{"id":255171,"name":"Katsuyoshi Takata","orcid":"0000-0001-6890-1276","position":7,"is_corresponding":false},{"id":257242,"name":"Chi-Shuen Chu","orcid":null,"position":8,"is_corresponding":false},{"id":255168,"name":"Martín A. Rivas","orcid":"0000-0002-9603-6897","position":9,"is_corresponding":false},{"id":308650,"name":"Amy Chadburn","orcid":"0000-0002-9499-8638","position":10,"is_corresponding":false},{"id":255172,"name":"Christian Steidl","orcid":"0000-0001-9842-9750","position":11,"is_corresponding":false},{"id":106831,"name":"David W. Scott","orcid":"0000-0002-0435-5947","position":12,"is_corresponding":false},{"id":246358,"name":"Robert G. Roeder","orcid":"0000-0003-3865-8572","position":13,"is_corresponding":false},{"id":36370,"name":"Christopher E. Mason","orcid":"0000-0002-1850-1642","position":14,"is_corresponding":false},{"id":237414,"name":"Wendy Béguelin","orcid":"0000-0002-4894-9229","position":15,"is_corresponding":false},{"id":237422,"name":"Ari Melnick","orcid":"0000-0002-8074-2287","position":16,"is_corresponding":false},{"id":1165438,"name":"Jie Li","orcid":"0000-0003-4121-6353","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:18:52.232318Z","pmid":"36824887","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}