biostudies-literatureSakthivel DNIDDK NIH HHSNHLBI NIH HHSNCI NIH HHSNIH HHSNIGMS NIH HHSeadj3145https://www.ebi.ac.uk/biostudies/studies/S-EPMC11296348biostudies-literatureUnknown10(31)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.Science advancesCaspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia.PMC11296348T32 DK060445T32 GM136560T32 HL170967R01 GM121389R21 CA256606P30 CA125123S10 OD028648Shin CSFlanagan JMRobichaux DJCharendoff CIPoreba MLopez KEDunne KPCarisey AFSalgar SBouchier-Hayes LHuang SCoutinho LEKeane FBrown-Suedel ANSakthivel DVargas-Hernandez ASherry KMLe BfalseCaspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia.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.2024-01-01T00:00:00Z2024 Aug2026-05-07T14:19:14.269Z2025-04-04T02:09:24.945ZS-EPMC112963483909397710.1126/sciadv.adj3145