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 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.

Chemoproteomics Identifies State-Dependent and Proteoform-Selective Caspase-2 Inhibitors

“…Programmed cell death or apoptosis is a tightly regulated biological process required for the removal of irreversibly damaged or unwanted cells. Caspases are cysteine aspartate proteases responsible for the initiation and execution of programmed cell death. − Caspase-mediated proteolysis has also been implicated in a number of nonapoptotic processes, including cellular activation, , differentiation, − cell proliferation, immune response, ,− cell cycle regulation, , and inflammation. , Human cancers, ,− neurodegenerative diseases, and monogenic disorders , have all been linked to aberrant caspase activity. Motivated by these numerous important and diverse functions, there is ongoing interest in the functional stratification of individual caspases.…”

Chemoproteomics identifies proteoform-selective caspase-2 inhibitors

“…Caspases are cysteine aspartate proteases responsible for the initiation and execution of programmed cell death [1][2][3] . Caspase-mediated proteolysis has also been implicated in a number of non-apoptotic processes, including cellular activation [4][5] , differentiation [6][7][8] , cell proliferation 9 , immune response 4,[10][11][12] , cell cycle regulation 9,13 , and inflammation 10,14 . Human cancers 9,[15][16][17] , neurodegenerative diseases 18 and monogenic disorders 4,12 have all been linked to aberrant caspase activity.…”

“…Caspase-mediated proteolysis has also been implicated in a number of non-apoptotic processes, including cellular activation [4][5] , differentiation [6][7][8] , cell proliferation 9 , immune response 4,[10][11][12] , cell cycle regulation 9,13 , and inflammation 10,14 . Human cancers 9,[15][16][17] , neurodegenerative diseases 18 and monogenic disorders 4,12 have all been linked to aberrant caspase activity. Motivated by these numerous important and diverse functions, there is ongoing interest in the functional stratification of individual caspases.…”