Mutant NPM1 modulates PDCD4 ubiquitination degradation and facilitates leukemogenesis.

PDCD4 is a nuclear-cytoplasmic shuttling protein. It functions as a protein translation inhibitor and regulates cancer development. Here, we show that PDCD4 interacts with NPM1. NPM1 mutation results in cytoplasmic localization of mutated protein, NPMc+, which plays critical roles in leukemogenesis. We demonstrate that NPMc+ induces abnormal localization of PDCD4 in the cytoplasm and accelerates its ubiquitination degradation. Additionally, we uncover the function of PDCD4 in regulating histone deacetylation and gene transcription in the nucleus. These results imply that NPMc+ may initiate leukemia at both the transcriptional and translational levels by modulating the mislocalization and degradation of PDCD4. Finally, we show that the use of PDCD4-derived peptides to block the interaction between NPMc+ and PDCD4 exhibits a promising therapeutic effect in NPM1-mutated acute myeloid leukemia (AML) mice. Our findings suggest that the NPMc+/PDCD4 complex could be a potential therapeutic target for this subtype of AML.