# Mutant NPM1 modulates PDCD4 ubiquitination degradation and facilitates leukemogenesis

## TL;DR

This study shows how a mutated protein, NPMc+, causes leukemia by altering another protein, PDCD4, and suggests a potential new treatment for a specific type of leukemia.

## Contribution

The study reveals a novel mechanism by which NPMc+ promotes leukemia through PDCD4 mislocalization and degradation, and proposes a peptide-based therapeutic strategy.

## Key findings

- NPMc+ causes cytoplasmic mislocalization and ubiquitination degradation of PDCD4.
- Blocking the NPMc+/PDCD4 interaction with peptides shows therapeutic promise in NPM1-mutated AML.
- PDCD4 regulates histone deacetylation and gene transcription in the nucleus.

## Abstract

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.

•NPMc+ regulates PDCD4 ubiquitination-mediated degradation to promote leukemogenesis•NPMc+ may induce leukemia at transcriptional and translational levels via PDCD4•Block PDCD4-NPMc+ interaction with peptide: promising therapeutic for NPM1-mut AML

NPMc+ regulates PDCD4 ubiquitination-mediated degradation to promote leukemogenesis

NPMc+ may induce leukemia at transcriptional and translational levels via PDCD4

Block PDCD4-NPMc+ interaction with peptide: promising therapeutic for NPM1-mut AML

Molecular biology; Cell biology