Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia.

Sakthivel, D.; Brown-Suedel, A. N.; Keane, F.; Huang, S.; Mc Sherry, K.; Charendoff, C. I.; Dunne, K. P.; Robichaux, D. J.; Le, B.; Shin, C. S.; Carisey, A. F.; Flanagan, J. M.; Bouchier-Hayes, L.

doi:10.1101/2023.05.29.542723

bioRxiv · 10.1101/2023.05.29.542723

Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia.

Sakthivel, D.·Brown-Suedel, A. N.·Keane, F.·Huang, S.·Mc Sherry, K.·Charendoff, C. I.·Dunne, K. P.·Robichaux, D. J.·Le, B.·Shin, C. S.·Carisey, A. F.·Flanagan, J. M.·Bouchier-Hayes, L.

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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 pro-apoptotic 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+ AML but not in NPM1wt cells. Strikingly, in NPM1c+ cells, loss of caspase-2 results in profound cell cycle arrest, differentiation, and down-regulation of stem cell pathways that regulate pluripotency including impairment in the AKT/mTORC1 and Wnt signaling pathways. In contrast, there were minimal differences in proliferation, differentiation, or the transcriptional profile of NPM1wt cells with and without caspase-2. Together, these results show that caspase-2 is essential for proliferation and self-renewal of AML cells that have mutated NPM1. This study demonstrates that caspase-2 is a major effector of NPM1c+ function and may even be a druggable target to treat NPM1c+ AML and prevent relapse.

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Sakthivel, D., Brown-Suedel, A. N., Keane, F., Huang, S., Mc Sherry, K., Charendoff, C. I., Dunne, K. P., Robichaux, D. J., Le, B., Shin, C. S., Carisey, A. F., Flanagan, J. M., Bouchier-Hayes, L.. 2023-05-30. Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia.. https://doi.org/10.1101/2023.05.29.542723

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