{"doi":"10.1038/s41392-021-00870-3","title":"Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia","abstract":"Despite high initial response rates, acute myeloid leukemia (AML) treated with the BCL-2-selective inhibitor venetoclax (VEN) alone or in combinations commonly acquires resistance. We performed gene/protein expression, metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN, and identified the activation of RAS/MAPK pathway, leading to increased stability and higher levels of MCL-1 protein, as a major acquired mechanism of VEN resistance. MCL-1 sustained survival and maintained mitochondrial respiration in VEN-RE cells, which had impaired electron transport chain (ETC) complex II activity, and MCL-1 silencing or pharmacologic inhibition restored VEN sensitivity. In support of the importance of RAS/MAPK activation, we found by single-cell DNA sequencing rapid clonal selection of RAS-mutated clones in AML patients treated with VEN-containing regimens. In summary, these findings establish RAS/MAPK/MCL-1 and mitochondrial fitness as key survival mechanisms of VEN-RE AML and provide the rationale for combinatorial strategies effectively targeting these pathways.","journal":"Signal Transduction and Targeted Therapy","year":2022,"id":232555,"datarank":0.787053610824073,"base_score":5.247024072160486,"endowment":5.247024072160486,"self_citation_contribution":0.787053610824073,"citation_network_contribution":0.0,"self_endowment_contribution":0.787053610824073,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":189,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.952,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":251632,"name":"Bridget Riley‐Gillis","orcid":"0000-0001-7338-1156","position":1,"is_corresponding":false},{"id":616829,"name":"Lina Han","orcid":null,"position":2,"is_corresponding":false},{"id":628405,"name":"Yannan Jia","orcid":"0000-0002-9192-7463","position":3,"is_corresponding":false},{"id":348914,"name":"Alessia Lodi","orcid":"0000-0002-2104-5713","position":4,"is_corresponding":false},{"id":839752,"name":"Haijiao Zhang","orcid":"0000-0002-0749-9866","position":5,"is_corresponding":false},{"id":843507,"name":"Saravanan Ganesan","orcid":"0000-0002-5773-1715","position":6,"is_corresponding":false},{"id":567516,"name":"Rongqing Pan","orcid":"0000-0002-9494-412X","position":7,"is_corresponding":false},{"id":232856,"name":"Sergej Konoplev","orcid":"0000-0002-8417-7393","position":8,"is_corresponding":false},{"id":680483,"name":"Shannon Sweeney","orcid":"0000-0001-7080-8716","position":9,"is_corresponding":false},{"id":251425,"name":"Jeremy Ryan","orcid":"0000-0002-3327-1283","position":10,"is_corresponding":false},{"id":456479,"name":"Yulia Jitkova","orcid":"0000-0003-1252-0604","position":11,"is_corresponding":false},{"id":843508,"name":"Kenneth Dunner","orcid":"0000-0001-7731-0013","position":12,"is_corresponding":false},{"id":280226,"name":"Shaun Grosskurth","orcid":null,"position":13,"is_corresponding":false},{"id":843509,"name":"Priyanka Vijay","orcid":"0000-0002-6032-9081","position":14,"is_corresponding":false},{"id":601227,"name":"Sujana Ghosh","orcid":null,"position":15,"is_corresponding":false},{"id":247610,"name":"Charles Lu","orcid":"0000-0002-3392-6024","position":16,"is_corresponding":false},{"id":536461,"name":"Wencai Ma","orcid":"0000-0002-2913-6732","position":17,"is_corresponding":false},{"id":694825,"name":"Stephen E. Kurtz","orcid":"0000-0003-4762-389X","position":18,"is_corresponding":false},{"id":270243,"name":"Vivian Ruvolo","orcid":"0000-0003-4363-7258","position":19,"is_corresponding":false},{"id":843510,"name":"Helen Ma","orcid":"0000-0002-0416-5115","position":20,"is_corresponding":false},{"id":844787,"name":"Connie C. Weng","orcid":null,"position":21,"is_corresponding":false},{"id":844788,"name":"Cassandra L. Ramage","orcid":null,"position":22,"is_corresponding":false},{"id":18329,"name":"Natalia Baran","orcid":"0000-0003-0618-4798","position":23,"is_corresponding":false},{"id":608512,"name":"Ce Shi","orcid":null,"position":24,"is_corresponding":false},{"id":691208,"name":"Tianyu Cai","orcid":"0000-0002-5271-3235","position":25,"is_corresponding":false},{"id":390329,"name":"R. Eric Davis","orcid":"0000-0001-7311-0065","position":26,"is_corresponding":false},{"id":475051,"name":"Venkata Lokesh Battula","orcid":"0000-0001-5415-9058","position":27,"is_corresponding":false},{"id":843511,"name":"Yingchang Mi","orcid":"0000-0002-5060-5070","position":28,"is_corresponding":false},{"id":843512,"name":"Jing Wang","orcid":"0000-0001-8218-3418","position":29,"is_corresponding":false},{"id":109577,"name":"Courtney D. DiNardo","orcid":"0000-0001-9003-0390","position":30,"is_corresponding":false},{"id":230405,"name":"Michael Andreeff","orcid":"0000-0002-1144-1958","position":31,"is_corresponding":false},{"id":844789,"name":"Jeffery W. Tyner","orcid":null,"position":32,"is_corresponding":false},{"id":456483,"name":"Aaron D. Schimmer","orcid":"0000-0003-4023-3899","position":33,"is_corresponding":false},{"id":35290,"name":"Anthony Letai","orcid":"0000-0002-1993-9013","position":34,"is_corresponding":false},{"id":819987,"name":"Rose Ann Padua","orcid":"0000-0001-9964-7864","position":35,"is_corresponding":false},{"id":230402,"name":"Carlos E. Bueso‐Ramos","orcid":"0000-0003-0180-7124","position":36,"is_corresponding":false},{"id":348916,"name":"Stefano Tiziani","orcid":"0000-0002-7230-0307","position":37,"is_corresponding":false},{"id":712619,"name":"Joel D. Leverson","orcid":"0000-0003-1162-724X","position":38,"is_corresponding":false},{"id":251637,"name":"Relja Popovic","orcid":"0000-0002-6880-0798","position":39,"is_corresponding":false},{"id":18373,"name":"Marina Konopleva","orcid":"0000-0002-9347-2212","position":40,"is_corresponding":false},{"id":628406,"name":"Qi Zhang","orcid":"0000-0002-7918-8952","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:21:18.683916Z","pmid":"35185150","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":[]}