Role of NPM in the Control of Genetic Stability and Tumorigenesis.

Nucleophosmin (NPM, B23, NO38) is a nucleolar protein directly implicated in cancer pathogenesis as the NPM gene is found mutated and rearranged in a number of haematological disorders. In addition, the region of chromosome 5 where NPM maps to (5q35) is deleted in a proportion of de novo human myelodysplastic syndromes (MDS), and loss of chromosome 5 is extremely frequent in therapy-related MDS (t-MDS). NPM is a multifunctional protein, and its role in oncogenesis is controversial as NPM has been attributed both oncogenic and tumour suppressive functions. To study the function of Npm in vivo, we generated a hypomorphic Npm mutant series [Npm+/− < Npmhy/hy < Npm−/−] in the mouse, and we found that Npm is essential for embryonic development and the maintenance of genomic stability. Npm−/− and Npmhy/hy mutants display aberrant organogenesis and die between E11.5 and E16.5 due to severe anemia resulting from defects in primitive haematopoiesis. Furthermore Npm inactivation leads to unrestricted centrosome duplication and genomic instability. We demonstrate that Npm is haploinsufficient in the control of genetic stability and that Npm heterozygosity accelerates oncogenesis both in vitro and in vivo. Importantly, Npm+/− mice develop a haematological syndrome with features of human MDS. Our findings unravel an essential developmental role for Npm and implicate its functional loss in tumourigenesis and MDS pathogenesis.