Cytoplasmic localization of NPM in myeloid leukemias is dictated by gain-of-function mutations that create a functional nuclear export signal

Oncogene
A R MarianoPier Giuseppe Pelicci

Abstract

Nucleophosmin (NPM) is a nucleus-cytoplasmic shuttling protein that is implicated in centrosome duplication, cell cycle progression and stress response. At the steady state, NPM localizes mainly in the nucleolus, where it forms a complex with different cellular proteins. One-third of acute myeloid leukemias (AML) are characterized by aberrant cytoplasmic localization of NPM, due to mutations within its last coding exon (exon 12) that cause a frameshift and the formation of novel C-termini. We report here our investigations on the molecular basis for the aberrant localization of mutated NPM. Alignment of the C-terminus of the various NPM mutants revealed the obligatory presence of four amino-acid residues that match a CRM1-dependent nuclear export signal (NES). Single alanine-substitutions at these sites provoked nuclear re-localization, while fusion of the mutated C-terminus to a heterologous nuclear protein induced CRM1-dependent cytoplasmic localization. Molecular characterization of one exceptional AML carrying cytoplasmic NPM and germ line exon 12 revealed a somatic mutation in the splicing donor site of exon 9 that caused the formation of a functional NES. It appears, therefore, that AMLs are frequently characterized by ga...Continue Reading

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Citations

Nov 30, 2007·Histochemistry and Cell Biology·Valentina SirriDanièle Hernandez-Verdun
Oct 2, 2007·Current Opinion in Oncology·Olga FrankfurtMartin S Tallman
Oct 15, 2014·Seminars in Hematology·Luca MazzarellaPier Giuseppe Pelicci
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Jul 16, 2008·The Journal of Cell Biology·Pier Paolo Di Fiore
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Mar 17, 2006·Cancer Research·Emanuela ColomboPier Giuseppe Pelicci
Jun 2, 2009·Journal of Proteome Research·Matthew C GageJohn B C Findlay
Apr 22, 2021·Leukemia·Brunangelo FaliniMaria Paola Martelli

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