Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

Identification and functional characterization of a cytoplasmic nucleophosmin leukaemic mutant generated by a novel exon-11 NPM1 mutation

Leukemia volume 21, pages 1099–1103 (2007)Cite this article

Nucleophosmin (NPM1) mutations occur in 50–60% of adult acute myeloid leukemia (AML) with normal karyotype.1, 2 About 40 NPM1 mutations2 have been so far identified, all clustering in exon-12. In spite of molecular heterogeneity, all mutations cause common changes at the C terminus of NPM mutants, i.e. loss of tryptophans 288 and 290 (or 290 alone) and creation of a new nuclear export signal (NES) motif.2 As a consequence, NPM mutants aberrantly accumulates in the cytoplasm of leukaemic cells;3, 4 hence, the term NPMc+ (cytoplasmic-positive) AML.1, 2 Here, we report on the identification and functional characterization of a cytoplasmic nucleophosmin mutant generated by a novel exon-11 NPM1 mutation in a patient with AML.

Cytoplasmic accumulation of exon-12 NPM mutants is dictated by the concerted action of C-terminal mutated tryptophans and the creation of a NES motif.3 Notably, both alterations were also present in the NPMVi2 mutant. In fact, the NPMVi2 mutation resulted in loss of the whole exon-12 of the NPM1 gene (encoding for the C-terminal aromatic region and the tryptophan residues 288 and 290 responsible for nucleolar binding). Moreover, the NESbase version 1.0 program5 identified a putative NES motif with the VxxxFxxLxI sequence (Figure 1a) at the C terminus of the predicted NPMVi2 mutant protein. Therefore, the NPMVi2 mutant has not only lost the ability to target nucleoli, but also gained enforced nuclear export capabilities. Accordingly, the images of pEGFP-NPMVi2-transfected cells are the same as those of NPM mutant A (Figure 2, middle left) with which mutant NPMVi2 shares common features. In contrast, they differ from the less frequent mutants retaining tryptophan 288 (e.g. NPM mutant E), which are capable of partial nucleolar localization (Figure 2, bottom left).

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

References

  1. Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 2005; 352: 254–266.

    Article  CAS  PubMed  Google Scholar 

  2. Falini B, Nicoletti I, Martelli MF, Mecucci C . Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biological and clinical features. Blood 2007; 109: 874–885.

    Article  CAS  PubMed  Google Scholar 

  3. Falini B, Bolli N, Shan J, Martelli MP, Liso A, Pucciarini A et al. Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML. Blood 2006; 107: 4514–4523.

    Article  CAS  PubMed  Google Scholar 

  4. Falini B, Martelli MP, Bolli N, Bonasso R, Ghia E, Pallotta MT et al. Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia. Blood 2006; 108: 1999–2005.

    Article  CAS  PubMed  Google Scholar 

  5. la Cour T, Gupta R, Rapacki K, Skriver K, Poulsen FM, Brunak S . NESbase version 1.0: a database of nuclear export signals. Nucleic Acids Res 2003; 31: 393–396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pasqualucci L, Liso A, Martelli MP, Bolli N, Pacini R, Tabarrini A et al. Mutated nucleophosmin detects clonal multilineage involvement in acute myeloid leukemia: Impact on WHO classification. Blood 2006; 108: 4146–4155.

    Article  CAS  PubMed  Google Scholar 

  7. Nishimura Y, Ohkubo T, Furuichi Y, Umekawa H . Tryptophans 286 and 288 in the C-terminal region of protein B23.1 are important for its nucleolar localization. Biosci Biotechnol Biochem 2002; 66: 2239–2242.

    Article  CAS  PubMed  Google Scholar 

  8. Grisendi S, Mecucci C, Falini B, Pandolfi PP . Nucleophosmin and cancer. Nat Rev Cancer 2006; 6: 493–505.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Supported by the Associazione Vicentina Leucemie e Linfomi (AVILL), Associazione Italiana per la Ricerca sul Cancro (AIRC) and the Federazione Monte dei Paschi di Siena. EA was recipient of a grant from ‘Fondazione Progetto Ematologia’ – Vicenza. NB is a recipient of a fellowship from FIRC (Federazione Italiana per la Ricerca sul Cancro). We are grateful to Dr A Montaldi for cytogenetic analysis, Dr S Roberti for statistical analysis, Dr GA Boyd for editorial assistance and Mrs I Frasson for excellent secretarial assistance. B Falini applied for a patent of the clinical use of NPM mutants.

Author information

Authors and Affiliations

  1. Department of Cell Therapy and Haematology, San Bortolo Hospital, Vicenza, Italy

    E Albiero, D Madeo, I Giaretta, E Di Bona & F Rodeghiero

  2. Section of Haematology and Immunology, University of Perugia, IBIT Foundation, Perugia, Italy

    N Bolli, M F Martelli & B Falini

  3. Institute of Internal Medicine, University of Perugia, Perugia, Italy. E-mails: faliniem@unipg.it or rodeghiero@hemato.ven.it,

    I Nicoletti

Authors
  1. E Albiero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Madeo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N Bolli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I Giaretta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E Di Bona
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M F Martelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. I Nicoletti
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. F Rodeghiero
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. B Falini
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Albiero, E., Madeo, D., Bolli, N. et al. Identification and functional characterization of a cytoplasmic nucleophosmin leukaemic mutant generated by a novel exon-11 NPM1 mutation. Leukemia 21, 1099–1103 (2007). https://doi.org/10.1038/sj.leu.2404597

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404597

This article is cited by

Search

Advanced search

Quick links