{"doi":"10.1101/2025.05.22.655396","title":"Therapy resistance in AML is mediated by cytoplasmic sequestration of the transcriptional repressor IRF2BP2","abstract":"Summary While the development of venetoclax with azacitidine (ven/aza) has improved AML therapy, drug resistance remains a major challenge. Notably, primary ven/aza-resistant AML are frequently reliant on MCL1, however, the underlying mechanisms remain unclear. Co-immunoprecipitation of MCL1 from ven/aza-resistant AML samples coupled with mass spectrometry analysis identified the transcriptional repressor Interferon Regulatory Factor 2 Binding Protein 2 (IRF2BP2) as an MCL1 binding partner. This interaction results in cytoplasmic IRF2BP2 localization and loss of transcriptional repression within ven/aza-resistant leukemic stem cells (LSC). Consequently, ven/aza-resistant LSC have increased IRF2BP2 target gene expression, including acyl-CoA synthetase long-chain family member 1 ( ACSL1 ), an essential rate-limiting enzyme for fatty acid oxidation (FAO). Inhibition of ACSL1 functionally impaired ven/aza-resistant LSC through a depletion of long-chain acyl-carnitine metabolites and FAO. Collectively, these data provide evidence for a previously undescribed mechanism by which MCL1 mediates IRF2BP2 cytoplasmic sequestration and consequent de-repression of ACSL1 , thereby promoting ven/aza-resistance in AML.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":566690,"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":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":869170,"name":"Mohd Minhajuddin","orcid":null,"position":1,"is_corresponding":false},{"id":225900,"name":"Brett M. Stevens","orcid":"0000-0002-9346-903X","position":2,"is_corresponding":false},{"id":225904,"name":"Austin E. Gillen","orcid":"0000-0003-2928-6308","position":3,"is_corresponding":false},{"id":1295249,"name":"Stephanie Gipson","orcid":null,"position":4,"is_corresponding":false},{"id":659878,"name":"Sweta B. Patel","orcid":"0000-0001-7082-7204","position":5,"is_corresponding":false},{"id":984670,"name":"Ian T. Shelton","orcid":"0000-0001-5974-2736","position":6,"is_corresponding":false},{"id":350222,"name":"Regan Miller","orcid":"0000-0003-1583-3251","position":7,"is_corresponding":false},{"id":833665,"name":"Ana Vujovic","orcid":"0000-0002-9117-9282","position":8,"is_corresponding":false},{"id":229307,"name":"Anna Krug","orcid":null,"position":9,"is_corresponding":false},{"id":1443315,"name":"Tracy Young","orcid":null,"position":10,"is_corresponding":false},{"id":1322254,"name":"William M. Showers","orcid":null,"position":11,"is_corresponding":false},{"id":438368,"name":"Monika Dzieciątkowska","orcid":"0000-0002-9947-2520","position":12,"is_corresponding":false},{"id":489004,"name":"Daniel Stephenson","orcid":"0000-0002-5698-3400","position":13,"is_corresponding":false},{"id":251810,"name":"Anit Tyagi","orcid":"0000-0001-9455-2591","position":14,"is_corresponding":false},{"id":983387,"name":"Jana M. Ellegast","orcid":"0000-0003-4201-4227","position":15,"is_corresponding":false},{"id":1205962,"name":"Tristen Wright","orcid":"0000-0001-8745-5777","position":16,"is_corresponding":false},{"id":268862,"name":"Kimberly Stegmaier","orcid":"0000-0003-0218-7895","position":17,"is_corresponding":false},{"id":254774,"name":"Joseph T. Opferman","orcid":"0000-0002-1147-5621","position":18,"is_corresponding":false},{"id":28360,"name":"Angelo D’Alessandro","orcid":"0000-0002-2258-6490","position":19,"is_corresponding":false},{"id":225919,"name":"Clayton A. Smith","orcid":"0000-0001-6478-4244","position":20,"is_corresponding":false},{"id":225920,"name":"Craig T. Jordan","orcid":"0000-0003-0869-3465","position":21,"is_corresponding":false},{"id":1212188,"name":"Mark J. Althoff","orcid":"0000-0003-4628-8444","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T02:56:40.491968Z","pmid":"40475530","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":[]}