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.

Delocalization and destabilization of the ARF tumor suppressor by the leukemia-associated NPM mutant / E. Colombo, P. Martinelli, R. Zamponi, D.C. Shing, P. Bonetti, L. Luzi, S. Volorio, L. Bernard, G. Pruneri, M. Alcalay, P.G. Pelicci. - In: CANCER RESEARCH. - ISSN 0008-5472. - 66:6(2006 Mar 15), pp. 3044-3050.

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

E. Colombo;P. Bonetti;G. Pruneri;M. Alcalay;P.G. Pelicci
2006

Abstract

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.
Acute myeloid leukemia (-assocd. NPM mutant ; delocalization and destabilization of Arf tumor suppressor by the leukemia-assocd. NPM mutant ; Cell nucleus ; Cytoplasm (AML-assocd. NPM mutant localizes mainly in the cytoplasm due to an alteration of its nucleus-cytoplasmic shuttling equil.) ; Cell cycle (arrest ; expression of the NPM mutant reduces the ability of Arf to initiate a p53 response and to induce cell cycle arrest) ; p53 Role: BSU (Biological study, unclassified), BIOL (Biological study) (expression of the NPM mutant reduces the ability of Arf to initiate a p53 response and to induce cell cycle arrest); Proteins Role: BSU (Biological study, unclassified), BIOL (Biological study)(gene arf, delocalization and destabilization ; delocalization and destabilization of Arf tumor suppressor by the leukemia-assocd. NPM mutant) ; Transformation (leukemogenesis ; Inactivation of p19Arf, might contribute to leukemogenesis in AMLs with mutated NPM) ; Proteins Role: BSU (Biological study, unclassified), BIOL (Biological study) (nucleophosmin, NPM mutant ; delocalization and destabilization of Arf tumor suppressor by the leukemia-assocd. NPM mutant) ; Proteins Role: BSU (Biological study, unclassified), BIOL (Biological study) (p19ARF, Inactivation; Inactivation of p19Arf, might contribute to leukemogenesis in AMLs with mutated NPM) ; Gene Role: BSU (Biological study, unclassified), BIOL (Biological study) (tumor suppressor, Arf ; delocalization and destabilization of Arf tumor suppressor by the leukemia-assocd. NPM mutant) ; nucleolar protein b23 ; non-hodgkins-lymphoma ; nuclear export ; nucleophosmin ; p53 ; fusion ; stability ; gene ; domain
Settore MED/04 - Patologia Generale
Settore MED/08 - Anatomia Patologica
15-mar-2006
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/64619
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