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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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.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
Targeted disruption of the Npm gene and Npm-/- embryos phenotype. (PDF 16787 kb)
Generation and phenotype of Npm hypomorphic mice. Ribosome profile of Npm deficient MEFs. (PDF 9321 kb)
Analysis of apoptosis and proliferation in E9.5 wt and Npm-/- embryos. (PDF 5617 kb)
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)
Npm+/- mice display myelodysplastic features. (PDF 2780 kb)
Full text legends to accompany the above Supplementary Figures. (DOC 32 kb)
Yolk sac progenitor cell differentiation assay. Ribosome profile analysis. (DOC 20 kb)
Genotypes of offspring from Npm+/- intercrosses. (DOC 23 kb)
Genotypes of offspring from Npm+/hy intercrosses. (DOC 21 kb)
Genotypes of offspring from Npm+/- p53+/- intercrosses. (DOC 22 kb)
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