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

A. R. Mariano, E. Colombo, L. Luzi, P. Martinelli, S. Volorio, L. Bernard, N. Meani, R. Bergomas, M. Alcalay, P. G. Pelicci

Research output: Contribution to journalArticle

50 Citations (Scopus)

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 gain-of-function mutations of NPM that create functional NES, suggesting that alterations of nuclear export might represent a general mechanism of leukemogenesis and a novel target for therapeutic intervention.

Original languageEnglish
Pages (from-to)4376-4380
Number of pages5
JournalOncogene
Volume25
Issue number31
DOIs
Publication statusPublished - Jul 20 2006

Fingerprint

Nuclear Export Signals
Myeloid Leukemia
Mutation
Exons
Acute Myeloid Leukemia
Centrosome
Cell Nucleus Active Transport
Nuclear Proteins
nucleophosmin
Germ Cells
Alanine
Cell Cycle
Proteins
Amino Acids

Keywords

  • AML
  • CRM1
  • NES
  • NPM
  • Nucleus-cytoplasmic shuttling

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Cytoplasmic localization of NPM in myeloid leukemias is dictated by gain-of-function mutations that create a functional nuclear export signal. / Mariano, A. R.; Colombo, E.; Luzi, L.; Martinelli, P.; Volorio, S.; Bernard, L.; Meani, N.; Bergomas, R.; Alcalay, M.; Pelicci, P. G.

In: Oncogene, Vol. 25, No. 31, 20.07.2006, p. 4376-4380.

Research output: Contribution to journalArticle

@article{633d77d768a24939a35fead975711f6d,
title = "Cytoplasmic localization of NPM in myeloid leukemias is dictated by gain-of-function mutations that create a functional nuclear export signal",
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 gain-of-function mutations of NPM that create functional NES, suggesting that alterations of nuclear export might represent a general mechanism of leukemogenesis and a novel target for therapeutic intervention.",
keywords = "AML, CRM1, NES, NPM, Nucleus-cytoplasmic shuttling",
author = "Mariano, {A. R.} and E. Colombo and L. Luzi and P. Martinelli and S. Volorio and L. Bernard and N. Meani and R. Bergomas and M. Alcalay and Pelicci, {P. G.}",
year = "2006",
month = "7",
day = "20",
doi = "10.1038/sj.onc.1209453",
language = "English",
volume = "25",
pages = "4376--4380",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "31",

}

TY - JOUR

T1 - Cytoplasmic localization of NPM in myeloid leukemias is dictated by gain-of-function mutations that create a functional nuclear export signal

AU - Mariano, A. R.

AU - Colombo, E.

AU - Luzi, L.

AU - Martinelli, P.

AU - Volorio, S.

AU - Bernard, L.

AU - Meani, N.

AU - Bergomas, R.

AU - Alcalay, M.

AU - Pelicci, P. G.

PY - 2006/7/20

Y1 - 2006/7/20

N2 - 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 gain-of-function mutations of NPM that create functional NES, suggesting that alterations of nuclear export might represent a general mechanism of leukemogenesis and a novel target for therapeutic intervention.

AB - 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 gain-of-function mutations of NPM that create functional NES, suggesting that alterations of nuclear export might represent a general mechanism of leukemogenesis and a novel target for therapeutic intervention.

KW - AML

KW - CRM1

KW - NES

KW - NPM

KW - Nucleus-cytoplasmic shuttling

UR - http://www.scopus.com/inward/record.url?scp=33645521836&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33645521836&partnerID=8YFLogxK

U2 - 10.1038/sj.onc.1209453

DO - 10.1038/sj.onc.1209453

M3 - Article

C2 - 16501600

AN - SCOPUS:33645521836

VL - 25

SP - 4376

EP - 4380

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 31

ER -