Language
English
Publication Date
8-2-2024
Journal
Science Advances
DOI
10.1126/sciadv.adj3145
PMID
39093977
PMCID
PMC11296348
PubMedCentral® Posted Date
8-2-2024
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Nucleophosmin, Leukemia, Myeloid, Acute, Nuclear Proteins, Caspase 2, Cell Proliferation, Humans, Mutation, Apoptosis, Animals, Cell Differentiation, Cell Line, Tumor, Cell Self Renewal, Mice, DNA Damage
Published Open-Access
yes
Recommended Citation
Sakthivel, Dharaniya; Brown-Suedel, Alexandra N; Lopez, Karla E; et al., "Caspase-2 Is Essential for Proliferation and Self-Renewal of Nucleophosmin-Mutated Acute Myeloid Leukemia" (2024). Faculty and Staff Publications. 3957.
https://digitalcommons.library.tmc.edu/baylor_docs/3957