Playing both sides: nucleophosmin between tumor suppression and oncogenesis

Abstract

Nucleophosmin (NPM) is frequently mutated in acute myeloid leukemias and is thought to act as both a proto-oncogene and a tumor suppressor. Although genetic and molecular evidence has shed light on the mechanisms of NPM-mediated tumor suppression, the potential role of NPM mutants as oncogenes remains ill defined. Now, new data provide a straightforward mechanism for this latter function, as NPM is shown to regulate the stability and the function of MYC. Remarkably, the same leitmotif of "placing a critical cell regulator in the wrong place at the wrong time" appears to underscore all the cancer-promoting activities of mutated NPM.

Figure 1.

Mutated NMP attenuates an oncosuppressor pathway and enhances an oncogenic one. Normal cell: NPM is mainly localized in the nucleolus and is required for nucleolar accumulation and stability of FBW7γ and ARF. This is relevant for the control of MYC turnover and provides an active pool of ARF ready to inactivate the HDM2-mediated p53 degradation in response to cellular stress. AML blast: NPM-mut is mainly localized to the cytoplasm and causes cytoplasmic delocalization and degradation of ARF and FBW7γ. As a consequence, HDM2 can induce ubiquitination/degradation of p53, and MYC accumulates and activates its target genes.