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Role of nucleophosmin in embryonic development and tumorigenesis

Nature volume 437, pages 147–153 (2005)Cite this article

Abstract

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 disorders1,2,3,4,5. Furthermore, the region of chromosome 5 to which NPM1 maps is deleted in a proportion of de novo human myelodysplastic syndromes (MDS)6,7,8,9, and loss of chromosome 5 is extremely frequent in therapy-related MDS9,10. NPM is a multifunctional protein11,12,13,14,15, and its role in oncogenesis is controversial as NPM has been attributed with both oncogenic and tumour suppressive functions16,17,18,19. To study the function of Npm in vivo, we generated a hypomorphic Npm1 mutant series (Npm1+/- < Npm1hy/hy < Npm1-/-) in mouse. Here we report that Npm is essential for embryonic development and the maintenance of genomic stability. Npm1-/- and Npm1hy/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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Figure 1: Npm1 inactivation causes developmental defects and embryonic lethality.
Figure 2: Effect of Npm1 inactivation on apoptosis, cell cycle and centrosome number.
Figure 3: Npm1 is haploinsufficient for the control of centrosome duplication and maintenance of genomic stability.
Figure 4: Npm1 +/- mice show myelodysplastic features.

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References

  1. Redner, R. L., Rush, E. A., Faas, S., Rudert, W. A. & Corey, S. J. The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood 87, 882–886 (1996)

    CAS  PubMed  Google Scholar 

  2. Morris, S. W. et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 263, 1281–1284 (1994)

    Article  ADS  CAS  Google Scholar 

  3. Yoneda-Kato, N. et al. The t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1. Oncogene 12, 265–275 (1996)

    CAS  PubMed  Google Scholar 

  4. Falini, B. et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N. Engl. J. Med. 352, 254–266 (2005)

    Article  CAS  Google Scholar 

  5. Grisendi, S. & Pandolfi, P. P. NPM mutations in acute myelogenous leukemia. N. Engl. J. Med. 352, 291–292 (2005)

    Article  CAS  Google Scholar 

  6. Van den Berghe, H. & Michaux, L. 5q-, twenty-five years later: a synopsis. Cancer Genet. Cytogenet. 94, 1–7 (1997)

    Article  CAS  Google Scholar 

  7. Westbrook, C. A. et al. Cytogenetic and molecular diagnosis of chromosome 5 deletions in myelodysplasia. Br. J. Haematol. 110, 847–855 (2000)

    Article  CAS  Google Scholar 

  8. Giagounidis, A. A. N. et al. Clinical, morphological, cytogenetic, and prognostic features of patients with myelodysplatic syndromes and del(5q) including band q31. Leukemia 18, 113–119 (2004)

    Article  CAS  Google Scholar 

  9. List, A. F., Vardiman, J., Issa, J. P. & DeWitte, T. M. Myelodysplastic syndromes. Hematology (Am. Soc. Hematol. Educ. Program), 297–317 (2004).

  10. Olney, H. J. & Le Beau, M. M. in The Myelodysplastic Syndromes, Pathobiology and Clinical Management (ed. Bennet, J. M.) 89–120 (Marcel Dekker, New York, 2002)

    Google Scholar 

  11. Hingorani, K., Szebeni, A. & Olson, M. O. Mapping the functional domains of nucleolar protein B23. J. Biol. Chem. 275, 24451–24457 (2000)

    Article  CAS  Google Scholar 

  12. Savkur, R. S. & Olson, M. O. Preferential cleavage in pre-ribosomal RNA by protein B23 endoribonuclease. Nucleic Acids Res. 26, 4508–4515 (1998)

    Article  CAS  Google Scholar 

  13. Wu, M. H. & Yung, B. Y. UV stimulation of nucleophosmin/B23 expression is an immediate-early gene response induced by damaged DNA. J. Biol. Chem. 277, 48234–48240 (2002)

    Article  CAS  Google Scholar 

  14. Zhang, H. et al. B23/nucleophosmin serine 4 phosphorylation mediates mitotic functions of polo-like kinase 1. J. Biol. Chem. 279, 35726–35734 (2004)

    Article  CAS  Google Scholar 

  15. Okuda, M. et al. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 103, 127–140 (2000)

    Article  CAS  Google Scholar 

  16. Kondo, T. et al. Identification and characterization of nucleophosmin/B23/numatrin which binds the anti-oncogenic transcription factor IRF-1 and manifests oncogenic activity. Oncogene 15, 1275–1281 (1997)

    Article  CAS  Google Scholar 

  17. Bertwistle, D., Sugimoto, M. & Sherr, C. J. Physical and functional interactions of the Arf tumour suppressor protein with nucleophosmin/B23. Mol. Cell. Biol. 24, 985–996 (2004)

    Article  CAS  Google Scholar 

  18. Colombo, E., Marine, J. C., Danovi, D., Falini, B. & Pelicci, P. G. Nucleophosmin regulates the stability and transcriptional activity of p53. Nature Cell Biol. 4, 529–533 (2002)

    Article  CAS  Google Scholar 

  19. Kurki, S. et al. Nucleolar protein NPM interacts with HDM2 and protects tumour suppressor protein p53 from HDM2-mediated degradation. Cancer Cell 5, 465–475 (2004)

    Article  CAS  Google Scholar 

  20. Mendes-da-Silva, P., Moreira, A., Duro-da-Costa, J., Matias, D. & Monteiro, C. Frequent loss of heterozygosity on chromosome 5 in non-small cell lung carcinoma. Mol. Pathol. 53, 184–187 (2000)

    Article  CAS  Google Scholar 

  21. Korgaonkar, C. et al. Nucleophosmin (B23) targets Arf to nucleoli and inhibits its function. Mol. Cell. Biol. 25, 1258–1271 (2005)

    Article  CAS  Google Scholar 

  22. Li, J., Zhang, X., Sejas, D. P., Bagby, G. C. & Pang, Q. Hypoxia-induced Nucleophosmin protects cell death through inhibition of p53. J. Biol. Chem. 279, 41275–41279 (2004)

    Article  CAS  Google Scholar 

  23. Lanni, J. S. & Jacks, T. Characterization of the p53-dependent postmitotic checkpoint following spindle disruption. Mol. Cell. Biol. 18, 1055–1064 (1998)

    Article  CAS  Google Scholar 

  24. Khan, S. H. & Whal, G. M. p53 and pRb prevent rereplication in response to microtubule inhibitors by mediating a reversible G1 arrest. Cancer Res. 58, 369–401 (1998)

    Google Scholar 

  25. Stewart, Z. A., Leach, S. D. & Pietenpol, J. A. p21(Waf1/Cip1) inhibition of cyclin E/Cdk2 activity prevents endoreduplication after mitotic spindle disruption. Mol. Cell. Biol. 19, 205–215 (1999)

    Article  CAS  Google Scholar 

  26. Spike, B. T. et al. The Rb tumour suppressor is required for stress erythropoiesis. EMBO J. 23, 4319–4329 (2004)

    Article  CAS  Google Scholar 

  27. Lerch-Gagg, A. et al. Pescadillo is essential for nucleolar assembly, ribosome biogenesis, and mammalian cell proliferation. J. Biol. Chem. 277, 45347–45355 (2002)

    Article  Google Scholar 

  28. Bunting, M., Bernstein, K. E., Greer, J. M., Capecchi, M. R. & Thomas, K. R. Targeting genes for self-excision in the germ line. Genes Dev. 13, 1524–1528 (1999)

    Article  CAS  Google Scholar 

  29. Bardeesy, N. et al. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 419, 162–167 (2002)

    Article  ADS  CAS  Google Scholar 

  30. Chung, Y. J. et al. A whole-genome mouse BAC microarray with 1-Mb resolution for analysis of DNA copy number changes by array comparative genomic hybridization. Genome Res. 14, 188–196 (2004)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to M. Leversha and A. Viale at the Molecular Cytogenetics and Genomics Core Facilities and J. Teruya-Feldstein for haematopathology consultation. We thank A. Walz, T. Merghoub, D. Ruggero, E. Hernando and C. Cordon-Cardo for help and advice; M. Capecchi, N. Bardeesy, R.A. Depinho and I. Zhon for reagents; T. Maeda, L. Montanaro, R. Hobbs, J. Clohessy, L. DiSantis, L. Longo and the other members of the P.P.P. laboratory for discussion, critical reading of the manuscript and support. This work was funded by National Institutes of Health grants to P.P.P.

Author information

Authors and Affiliations

  1. Department of Pathology, Cancer Biology and Genetics Program,

    Silvia Grisendi, Rosa Bernardi, Ke Cheng, Luipa Khandker & Pier Paolo Pandolfi

  2. Department of Medicine, Laboratory of Cellular Immunobiology,

    Marco Rossi

  3. Developmental Biology Program, Molecular Cytology Core Facility, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Katia Manova

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  1. Silvia Grisendi
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Correspondence to Pier Paolo Pandolfi.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure S1

Targeted disruption of the Npm gene and Npm-/- embryos phenotype. (PDF 16787 kb)

Supplementary Figure S2

Generation and phenotype of Npm hypomorphic mice. Ribosome profile of Npm deficient MEFs. (PDF 9321 kb)

Supplementary Figure S3

Analysis of apoptosis and proliferation in E9.5 wt and Npm-/- embryos. (PDF 5617 kb)

Supplementary Figure S4

Aneuploidy and tumour susceptibility in Npm deficient MEFs. CGH Array and LOH analysis of Npm+/+ Eµ-Myc and Npm+/- Eµ-Myc lymphomas. (PDF 2886 kb)

Supplementary Figure S5

Npm+/- mice display myelodysplastic features. (PDF 2780 kb)

Supplementary Figure Legends

Full text legends to accompany the above Supplementary Figures. (DOC 32 kb)

Supplementary Methods

Yolk sac progenitor cell differentiation assay. Ribosome profile analysis. (DOC 20 kb)

Supplementary Table S1

Genotypes of offspring from Npm+/- intercrosses. (DOC 23 kb)

Supplementary Table S2

Genotypes of offspring from Npm+/hy intercrosses. (DOC 21 kb)

Supplementary Table S3

Genotypes of offspring from Npm+/- p53+/- intercrosses. (DOC 22 kb)

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Grisendi, S., Bernardi, R., Rossi, M. et al. Role of nucleophosmin in embryonic development and tumorigenesis. Nature 437, 147–153 (2005). https://doi.org/10.1038/nature03915

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