Delocalization and destabilization of the ARF tumor suppressor by the leukemia-associated NPM mutant

One-third of acute myeloid leukemias (AML) are characterized by the aberrant cytoplasmic localization of Nucleophosmin (NPM), due to mutations within its putative nucleolar localization signal. NPM mutations are mutually exclusive with major AML-associated chromosome rearrangements, and are frequently associated with a normal karyotype, suggesting that they are critical during leukemogenesis. The underlying molecular mechanisms are, however, unknown. NPM is a nucleo-cytoplasmic shuttling protein that has been implicated in several cellular processes, including ribosome biogenesis, centrosome duplication, cell cycle progression and stress response. It has been recently shown that NPM is required for the stabilization and proper nucleolar localization of the tumor suppressor p19Arf. We report here that the AML-associated NPM mutant localizes mainly in the cytoplasm, due to an alteration of its nucleus-cytoplasmic shuttling equilibrium, forms a direct complex with p19Arf, but is unable to protect it from degradation. As a consequence, cells or leukemic blasts expressing the NPM mutant have low levels of cytoplasmic Arf. Inactivation of p19Arf, a key regulator of the p53-dependent cellular response to oncogene expression, might therefore contribute to leukemogenesis in AMLs with mutated NPM.