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Acute Leukemias

A dose-dependent tug of war involving the NPM1 leukaemic mutant, nucleophosmin, and ARF

Abstract

In acute myeloid leukaemia (AML), nucleophosmin-1 (NPM1) mutations create a nuclear export signal (NES) motif and disrupt tryptophans at NPM1 C-terminus, leading to nucleophosmin accumulation in leukaemic cell cytoplasm. We investigated how nucleophosmin NES motifs (two physiological and one created by the mutation) regulate traffic and interaction of mutated NPM1, NPM1wt and p14ARF. Nucleophosmin export into cytoplasm was maximum when the protein contained all three NES motifs, as naturally occurs in NPM1-mutated AML. The two physiological NES motifs mediated NPM1 homo/heterodimerization, influencing subcellular distribution of NPM1wt, mutated NPM1 and p14ARF in a ‘dose-dependent tug of war’ fashion. In transfected cells, excess doses of mutant NPM1 relocated completely NPM1wt (and p14ARF) from the nucleoli to the cytoplasm. This distribution pattern was also observed in a proportion of NPM1-mutated AML patients. In transfected cells, excess of NPM1wt (and p14ARF) relocated NPM1 mutant from the cytoplasm to the nucleoli. Notably, this distribution pattern was not observed in AML patients where the mutant was consistently cytoplasmic restricted. These findings reinforce the concept that NPM1 mutants are naturally selected for most efficient cytoplasmic export, pointing to this event as critical for leukaemogenesis. Moreover, they provide a rationale basis for designing small molecules acting at the interface between mutated NPM1 and other interacting proteins.

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Acknowledgements

This study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, and by the Fondazione Cassa di Risparmio di Perugia. We are grateful to Dr GA Boyd for editorial assistance. B Falini has applied for a patent on the clinical use of NPM1 mutants. N Bolli is recipient of a Fellowship from FIRC (Federazione Italiana per la Ricerca sul Cancro).

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Correspondence to B Falini.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Bolli, N., De Marco, M., Martelli, M. et al. A dose-dependent tug of war involving the NPM1 leukaemic mutant, nucleophosmin, and ARF. Leukemia 23, 501–509 (2009). https://doi.org/10.1038/leu.2008.326

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