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

Emanuela Colombo, Paola Martinelli, Raffaella Zamponi, Danielle C. Shing, Paola Bonetti, Lucilla Luzi, Sara Volorio, Loris Bernard, Giancarlo Pruneri, Myriam Alcalay, Pier Giuseppe Pelicci

Research output: Contribution to journalArticlepeer-review

Abstract

One third of acute myeloid leukemias (AMLs) 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 nucleocytoplasmic 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 p19 Arf. 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 p19 Arf, but is unable to protect it from degradation. Consequently, cells or leukemic blasts expressing the NPM mutant have low levels of cytoplasmic Arf. Furthermore, we show that expression of the NPM mutant reduces the ability of Arf to initiate a p53 response and to induce cell cycle arrest. Inactivation of p19 Arf, a key regulator of the p53-dependent cellular response to oncogene expression, might therefore contribute to leukemogenesis in AMLs with mutated NPM.

Original languageEnglish
Pages (from-to)3044-3050
Number of pages7
JournalCancer Research
Volume66
Issue number6
DOIs
Publication statusPublished - Mar 15 2006

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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