Nucleophosmin: from structure and function to disease development

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Abstract

Nucleophosmin (NPM1) is a critical cellular protein that has been implicated in a number of pathways including mRNA transport, chromatin remodeling, apoptosis and genome stability. NPM1 function is a critical requirement for normal cellular biology as is underlined in cancer where NPM1 is commonly overexpressed, mutated, rearranged and sporadically deleted. Consistent with a multifunctional role within the cell, NPM1 can function not only as a proto-oncogene but also as a tumor suppressor. The aim of this review is to look at the less well-described role of NPM1 in the DNA repair pathways as well as the role of NPM1 in the regulation of apoptosis and its mutation in cancers.

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Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype.

Brunangelo Falini, Cristina Mecucci, Enrico Tiacci … (2005)

Nucleophosmin (NPM), a nucleocytoplasmic shuttling protein with prominent nucleolar localization, regulates the ARF-p53 tumor-suppressor pathway. Translocations involving the NPM gene cause cytoplasmic dislocation of the NPM protein. We used immunohistochemical methods to study the subcellular localization of NPM in bone marrow-biopsy specimens from 591 patients with primary acute myelogenous leukemia (AML). We then correlated the presence of cytoplasmic NPM with clinical and biologic features of the disease. Cytoplasmic NPM was detected in 208 (35.2 percent) of the 591 specimens from patients with primary AML but not in 135 secondary AML specimens or in 980 hematopoietic or extrahematopoietic neoplasms other than AML. It was associated with a wide spectrum of morphologic subtypes of the disease, a normal karyotype, and responsiveness to induction chemotherapy, but not with recurrent genetic abnormalities. There was a high frequency of FLT3 internal tandem duplications and absence of CD34 and CD133 in AML specimens with a normal karyotype and cytoplasmic dislocation of NPM, but not in those in which the protein was restricted to the nucleus. AML specimens with cytoplasmic NPM carried mutations of the NPM gene that were predicted to alter the protein at its C-terminal; this mutant gene caused cytoplasmic localization of NPM in transfected cells. Cytoplasmic NPM is a characteristic feature of a large subgroup of patients with AML who have a normal karyotype, NPM gene mutations, and responsiveness to induction chemotherapy. Copyright 2005 Massachusetts Medical Society.

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Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.

S Morris, M Kirstein, M B Valentine … (1994)

The 2;5 chromosomal translocation occurs in most anaplastic large-cell non-Hodgkin's lymphomas arising from activated T lymphocytes. This rearrangement was shown to fuse the NPM nucleolar phosphoprotein gene on chromosome 5q35 to a previously unidentified protein tyrosine kinase gene, ALK, on chromosome 2p23. In the predicted hybrid protein, the amino terminus of nucleophosmin (NPM) is linked to the catalytic domain of anaplastic lymphoma kinase (ALK). Expressed in the small intestine, testis, and brain but not in normal lymphoid cells, ALK shows greatest sequence similarity to the insulin receptor subfamily of kinases. Unscheduled expression of the truncated ALK may contribute to malignant transformation in these lymphomas.

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Role of nucleophosmin in embryonic development and tumorigenesis.

Silvia Grisendi, Rosa Bernardi, Marco Rossi … (2005)

Nucleophosmin (also known as NPM, B23, NO38) is a nucleolar protein directly implicated in cancer pathogenesis, as the NPM1 gene is found mutated and rearranged in a number of haematological disorders. Furthermore, the region of chromosome 5 to which NPM1 maps is deleted in a proportion of de novo human myelodysplastic syndromes (MDS), and loss of chromosome 5 is extremely frequent in therapy-related MDS. NPM is a multifunctional protein, and its role in oncogenesis is controversial as NPM has been attributed with both oncogenic and tumour suppressive functions. To study the function of Npm in vivo, we generated a hypomorphic Npm1 mutant series (Npm1+/- < Npm1(hy/hy) < Npm1-/-) in mouse. Here we report that Npm is essential for embryonic development and the maintenance of genomic stability. Npm1-/- and Npm1(hy/hy) mutants have aberrant organogenesis and die between embryonic day E11.5 and E16.5 owing to severe anaemia resulting from defects in primitive haematopoiesis. We show that Npm1 inactivation leads to unrestricted centrosome duplication and genomic instability. We demonstrate that Npm is haploinsufficient in the control of genetic stability and that Npm1 heterozygosity accelerates oncogenesis both in vitro and in vivo. Notably, Npm1+/- mice develop a haematological syndrome with features of human MDS. Our findings uncover an essential developmental role for Npm and implicate its functional loss in tumorigenesis and MDS pathogenesis.

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Author and article information

Contributors

Joseph K. Box: j3.box@qut.edu.au

Nicolas Paquet: +61 7 3443 7236 , nicolas.paquet@qut.edu.au

Mark N. Adams: mn.adams@qut.edu.au

Didier Boucher: didier.boucher@qut.edu.au

Emma Bolderson: emma.bolderson@qut.edu.au

Kenneth J. O’Byrne: k.obyrne@qut.edu.au

Derek J. Richard:

ORCID: http://orcid.org/0000-0002-4839-8471

+61 7 3443 7236 , derek.richard@qut.edu.au

Journal

Journal ID (nlm-ta): BMC Mol Biol

Journal ID (iso-abbrev): BMC Mol. Biol

Title: BMC Molecular Biology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2199

Publication date (Electronic): 24 August 2016

Publication date PMC-release: 24 August 2016

Publication date Collection: 2016

Volume: 17

Issue: 1

Electronic Location Identifier: 19

Affiliations

School of Biomedical Research, Institute of Health and Biomedical Innovation at the Translational Research Institute, Queensland University of Technology, Brisbane, QLD Australia

Author information

Derek J. Richard http://orcid.org/0000-0002-4839-8471

Article

Publisher ID: 73

DOI: 10.1186/s12867-016-0073-9

PMC ID: 4995807

PubMed ID: 27553022

SO-VID: dbb1f6c2-5559-4ac1-8296-7b02a0159f46

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 8 May 2016

Date accepted : 16 August 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;

Award ID: 1066550

Award ID: 1091589

Award Recipient : Mark N. Adams Derek J. Richard

Funded by: FundRef http://dx.doi.org/10.13039/501100000923, Australian Research Council;

Award ID: DP 120103099

Award Recipient : Derek J. Richard

Funded by: Queensland Government (AU)

Funded by: Advance Queensland Research fellowship

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ScienceOpen disciplines: Molecular biology

Keywords: nucleophosmin 1,dna repair,cancer,apoptosis

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ScienceOpen disciplines: Molecular biology

Keywords: nucleophosmin 1, dna repair, cancer, apoptosis

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Nucleophosmin: from structure and function to disease development

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Higher order chromatin architecture

Most cited references 93

Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype.

Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.

Role of nucleophosmin in embryonic development and tumorigenesis.

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