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Letter

Nature 437, 147-153 (1 September 2005) | doi:10.1038/nature03915; Received 23 February 2005; Accepted 14 June 2005; Published online 6 July 2005

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Role of nucleophosmin in embryonic development and tumorigenesis

Silvia Grisendi1, Rosa Bernardi1, Marco Rossi2, Ke Cheng1, Luipa Khandker1, Katia Manova3 & Pier Paolo Pandolfi1

  1. Cancer Biology and Genetics Program, Department of Pathology,
  2. Laboratory of Cellular Immunobiology, Department of Medicine, and
  3. Developmental Biology Program, Molecular Cytology Core Facility, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA

Correspondence to: Pier Paolo Pandolfi1 Correspondence and requests for materials should be addressed to P.P.P. (Email: p-pandolfi@ski.mskcc.org).

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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.