{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Sakthivel D"],"funding":["NIDDK NIH HHS","NHLBI NIH HHS","NCI NIH HHS","NIH HHS","NIGMS NIH HHS"],"pagination":["eadj3145"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11296348"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["10(31)"],"pubmed_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 <i>NPM1c+</i> but not in <i>NPM1wt</i> AML cells. Strikingly, in <i>NPM1c</i>+ 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 <i>NPM1wt</i> 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"],"pubmed_title":["Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia."],"pmcid":["PMC11296348"],"funding_grant_id":["T32 DK060445","T32 GM136560","T32 HL170967","R01 GM121389","R21 CA256606","P30 CA125123","S10 OD028648"],"pubmed_authors":["Shin CS","Flanagan JM","Robichaux DJ","Charendoff CI","Poreba M","Lopez KE","Dunne KP","Carisey AF","Salgar S","Bouchier-Hayes L","Huang S","Coutinho LE","Keane F","Brown-Suedel AN","Sakthivel D","Vargas-Hernandez A","Sherry KM","Le B"],"additional_accession":[]},"is_claimable":false,"name":"Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia.","description":"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 <i>NPM1c+</i> but not in <i>NPM1wt</i> AML cells. Strikingly, in <i>NPM1c</i>+ 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 <i>NPM1wt</i> 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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Aug","modification":"2026-05-07T14:19:14.269Z","creation":"2025-04-04T02:09:24.945Z"},"accession":"S-EPMC11296348","cross_references":{"pubmed":["39093977"],"doi":["10.1126/sciadv.adj3145"]}}