The nucleolar protein nucleophosmin (NPM) is mutated or translocated in several human haematological malignancies including myelodysplastic syndrome (MDS). By studying the role of NPM in mice, Pier Paolo Pandolfi and colleagues have shown that it is essential for mouse embryogenesis and that it might also have a role in the pathogenesis of human MDS.

Knocking out Npm1 was lethal at around embryonic day 12. Studies revealed that this was at least partly caused by NPM being required for successful forebrain and haematopoetic development. The initiation of apoptosis — which was attributed to centrosome abnormalities — and ribosome-biogenesis defects in Npm1−/− tissues was accompanied by a marked upregulation of p53 that probably contributed to this phenotype.

On a cellular level, NPM was shown to be crucial for maintaining genomic stability, as Npm1−/− cells underwent a p53-mediated cell-cycle arrest caused by tetraploidy, as well as a significant degree of centrosome amplification and defects in the mitotic spindle. Furthermore, Npm1 gene dosage is important for this function, as similar genomic defects were seen in Npm1+/− cells, and resulted in those cells being more susceptible to oncogenic transformation both in vitro and in vivo. The authors therefore suggest that the genetic instability that is caused by NPM deficiency — leading to unrestrained centrosome duplication and consequent aneuploidy — could contribute to tumorigenesis. This is particularly significant as Npm1+/− cells reflect the situation that occurs in human cancers in which the NPM1 locus is translocated or deleted.

Because NPM was shown to be haploinsufficient, the authors wanted to find out if haematopoesis was affected in Npm1+/− mice. Indeed, analysis of the blood and bone marrow of these mice revealed several dysplastic features that were reminiscent of the pathogenesis of human MDS. As the NPM1 locus on chromosome 5 is subject to structural aberrations in patients with MDS, the authors propose that NPM dysfunction might be a participating factor in the pathogenesis of this multigenic disease.