{"doi":"10.1126/sciadv.adj3145","title":"Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia","abstract":"Mutation in nucleophosmin (NPM1) causes relocalization of this normally nucleolar protein to the cytoplasm (NPM1c+). Despite NPM1 mutation being the most common driver mutation in cytogenetically normal adult acute myeloid leukemia (AML), the mechanisms of NPM1c+-induced leukemogenesis remain unclear. Caspase-2 is a proapoptotic protein activated by NPM1 in the nucleolus. Here, we show that caspase-2 is also activated by NPM1c+ in the cytoplasm and DNA damage–induced apoptosis is caspase-2 dependent in NPM1c+ but not in NPM1wt AML cells. Strikingly, in NPM1c + cells, caspase-2 loss results in profound cell cycle arrest, differentiation, and down-regulation of stem cell pathways that regulate pluripotency including impairment of the AKT/mTORC1 pathways, and inhibition of Rictor cleavage. In contrast, there were minimal differences in proliferation, differentiation, or the transcriptional profile of NPM1wt cells lacking caspase-2. Our results show that caspase-2 is essential for proliferation and self-renewal of AML cells expressing mutated NPM1. This study demonstrates that caspase-2 is a major effector of NPM1c+ function.","journal":"Science Advances","year":2024,"id":462172,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9528,"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":321727,"name":"Alexandra N. Brown-Suedel","orcid":null,"position":1,"is_corresponding":false},{"id":638912,"name":"Karla E. Rojas López","orcid":"0000-0001-7301-5260","position":2,"is_corresponding":false},{"id":879466,"name":"Suruchi Salgar","orcid":"0000-0003-0762-3051","position":3,"is_corresponding":false},{"id":1292033,"name":"Luiza E. Coutinho","orcid":null,"position":4,"is_corresponding":false},{"id":1172328,"name":"Francesca Keane","orcid":null,"position":5,"is_corresponding":false},{"id":2210,"name":"Shixia Huang","orcid":"0000-0003-2878-4129","position":6,"is_corresponding":false},{"id":1171975,"name":"Kenneth Mc Sherry","orcid":"0009-0000-6904-048X","position":7,"is_corresponding":false},{"id":574285,"name":"Chloé I. Charendoff","orcid":null,"position":8,"is_corresponding":false},{"id":1171976,"name":"Kevin Dunne","orcid":"0009-0003-0393-8037","position":9,"is_corresponding":false},{"id":1171977,"name":"Dexter Robichaux","orcid":"0000-0002-4807-459X","position":10,"is_corresponding":false},{"id":281959,"name":"Alexander Vargas‐Hernández","orcid":"0000-0002-8409-4862","position":11,"is_corresponding":false},{"id":1172329,"name":"BaoChau Le","orcid":null,"position":12,"is_corresponding":false},{"id":722258,"name":"Crystal S. Shin","orcid":"0000-0003-4533-4242","position":13,"is_corresponding":false},{"id":245874,"name":"Alexandre F. Carisey","orcid":"0000-0003-1326-2205","position":14,"is_corresponding":false},{"id":939143,"name":"Marcin Poręba","orcid":"0000-0002-0214-6252","position":15,"is_corresponding":false},{"id":573776,"name":"Jonathan M. Flanagan","orcid":"0000-0003-1330-6618","position":16,"is_corresponding":false},{"id":230333,"name":"Lisa Bouchier‐Hayes","orcid":"0000-0003-3886-5977","position":17,"is_corresponding":false},{"id":1072891,"name":"Dharaniya Sakthivel","orcid":"0000-0002-3632-1688","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-19T02:04:20.631898Z","pmid":"39093977","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":[]}