{"doi":"10.1101/2024.01.29.577409","title":"The ESCRT protein CHMP5 promotes T cell leukemia by controlling BRD4-p300-dependent transcription","abstract":"Summary Oncogene activity rewires cellular transcription, creating new transcription networks to which cancer cells become addicted, by mechanisms that are still poorly understood. Using human and mouse models of T cell acute lymphoblastic leukemia (T-ALL), we identify an essential nuclear role for CHMP5, a cytoplasmic endosomal sorting complex required for transport (ESCRT) protein, in establishing and maintaining the T-ALL transcriptional program. Nuclear CHMP5 promoted the T-ALL gene program by augmenting recruitment of the co-activator BRD4 by the histone acetyl transferase p300 selectively at enhancers and super-enhancers, an interaction that potentiated H3K27 acetylation at these regulatory enhancers. Consequently, loss of CHMP5 diminished BRD4 occupancy at enhancers and super-enhancers and impaired RNA polymerase II pause release, which resulted in downregulation of key T-ALL genes, notably MYC . Reinforcing its importance in T-ALL pathogenesis, CHMP5 deficiency mitigated chemoresistance in human T-ALL cells and abrogated T-ALL induction by oncogenic NOTCH1 in vivo . Thus, the ESCRT protein CHMP5 is an essential positive regulator of the transcriptional machinery promoting T-ALL disease. Graphical abstract Highlights Identification of a nuclear role for the cytosolic ESCRT protein CHMP5 in transcription CHMP5 mediates BRD4-dependent Pol II pause release and transcription of T-ALL genes P300-BRD4 induced enhancer and super-enhancer H3K27 acetylation requires CHMP5 CHMP5 depletion mitigates chemoresistance and abrogates T-ALL initiation in vivo","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":493919,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9476,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":887599,"name":"Shashikala Ratnayake","orcid":null,"position":1,"is_corresponding":false},{"id":24045,"name":"Qianzi Tang","orcid":"0000-0003-3235-3372","position":2,"is_corresponding":false},{"id":618684,"name":"Rui Wang","orcid":"0000-0002-5356-9685","position":3,"is_corresponding":false},{"id":719639,"name":"Ballachanda N. Devaiah","orcid":"0000-0003-1845-8418","position":4,"is_corresponding":false},{"id":232421,"name":"Lan Zhou","orcid":"0000-0002-9883-135X","position":5,"is_corresponding":false},{"id":418267,"name":"Qingrong Chen","orcid":"0000-0003-1325-6147","position":6,"is_corresponding":false},{"id":418276,"name":"Daoud Meerzaman","orcid":"0000-0002-0129-5256","position":7,"is_corresponding":false},{"id":290723,"name":"Dinah S. Singer","orcid":"0000-0002-7369-3018","position":8,"is_corresponding":false},{"id":345638,"name":"Stanley Adoro","orcid":"0000-0001-9092-5960","position":9,"is_corresponding":false},{"id":691197,"name":"Katharine Umphred-Wilson","orcid":"0000-0001-6416-0466","position":0,"is_corresponding":true}],"reference_count":100,"raw_metadata":null,"created_at":"2026-07-19T02:09:07.920649Z","pmid":"38352301","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":[]}