Nucleophosmin and its complex network: a possible therapeutic target in hematological diseases

Nucleophosmin (NPM, also known as B23, numatrin or NO38) is a ubiquitously expressed phosphoprotein belonging to the nucleoplasmin family of chaperones. NPM is mainly localized in the nucleolus where it exerts many of its functions, but a proportion of the protein continuously shuttles between the nucleus and the cytoplasm. A growing number of cellular proteins have been described as physical interactors of NPM, and consequently, NPM is thought to have a relevant role in diverse cellular functions, including ribosome biogenesis, centrosome duplication, DNA repair and response to stress. NPM has been implicated in the pathogenesis of several human malignancies and intriguingly, it has been described both as an activating oncogene and a tumor suppressor, depending on cell type and protein levels. In fact, increased NPM expression is associated with different types of solid tumors whereas an impairment of NPM function is characteristic of a subgroup of hematolologic malignancies. A large body of experimental evidence links the deregulation of specific NPM functions to cellular transformation, yet the molecular mechanisms through which NPM contributes to tumorigenesis remain elusive. In this review, we have summarized current knowledge concerning NPM functions, and attempted to interpret its multifaceted and sometimes apparently contradictory activities in the context of both normal cellular homeostasis and neoplastic transformation.