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Acute Leukemias

Nucleophosmin/B26 regulates PTEN through interaction with HAUSP in acute myeloid leukemia

Leukemia volume 27, pages 1037–1043 (2013)Cite this article

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Abstract

PTEN (phosphatase and tensin homolog deleted in chromosome 10) is a bona fide dual lipid and protein phosphatase with cytoplasmic (Cy) and nuclear localization. PTEN nuclear exclusion has been associated with tumorigenesis. Nucleophosmin (NPM1) is frequently mutated in acute myeloid leukemia (AML) and displays Cy localization in mutated nucleophosmin (NPMc+) AML. Here we show that NPM1 directly interacts with herpes virus-associated ubiquitin specific protease (HAUSP), which is known as a PTEN deubiquitinating enzyme. Strikingly, PTEN is aberrantly localized in AML carrying NPMc+. Mechanistically, NPM1 in the nucleus opposes HAUSP-mediated deubiquitination and this promotes the shuttle of PTEN to the cytoplasm. In the cytoplasm, NPMc+ prevents HAUSP from deubiquitinating PTEN, causing the latter to stay in the cytoplasm where it is polyubiquitinated and degraded. Our findings delineate a new NPM1–HAUSP molecular interaction controlling PTEN deubiquitination and trafficking.

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Acknowledgements

We are grateful to AM Gruszka (I.F.O.M. Milan) for kindly donating the T26 monoclonal antibody. This work was supported by AIRC (Associazione Italiana per la Ricerca sul Cancro), AIL (Associazione Italiana contro le Leucemie) and ANPCyT–FONCyT (Agencia Nacional de Promoción Científica y Tecnológica–Fondo para la Investigación Científica y Tecnológica, Argentina, PICT 2006-01865). This work was also supported by National Institutes of Health grants to PPP; KLC is a research fellow of the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); NIN and FG are established investigators at CONICET.

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Authors and Affiliations

  1. Neuro-Oncoematology Unit, Santa Lucia Foundation, Rome, Italy

    N I Noguera, T Ottone, I Faraoni & F Lo-Coco

  2. Hematology Department of Chemical Biochemistry, Rosario National University, Rosario, Argentina

    N I Noguera & K L Calvo

  3. Beth Israel Deaconess Cancer Center and Department of Medicine, Cancer Genetics Program, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    M S Song & P P Pandolfi

  4. Department of Biopathology, ‘Tor Vergata,’ University, Rome, Italy

    M Divona, G Catalano, T Ottone, S Amadori & F Lo-Coco

  5. Immunology Institute, Medical School, Rosario National University, Rosario, Argentina

    F García

  6. Confocal Microscopy Unit, EBRI-Santa Lucia Foundation, Rome, Italy

    F Florenzano

  7. Department of Neuroscience, ‘Tor Vergata’ University, Rome, Italy

    I Faraoni

  8. Neuroimmunology Unit, Fondazione Santa Lucia, Rome, Italy

    L Battistini

  9. Department of Experimental Oncology, European Institute of Oncology, Milan, Italy

    E Colombo

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  1. N I Noguera
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Correspondence to N I Noguera.

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Author Contributions

NIN designed, carried out and analyzed the experiments and co-wrote the manuscript. MSS carried out and analyzed the experiments and contributed in manuscript writing; MD and TO contributed with immunofluorescence analysis of patients samples; KLC, FG and IF carried out the experiments of western blot; FF performed the FRET analysis, analyzed the data and co-wrote the manuscript; GC contributed data analysis, interpretation of results and manuscript writing; LB, EC, and SA critically reviewed the manuscript, and amended the final report; FL-C. and PPP designed the study, supervised the research, co-wrote and edited the manuscript.

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Noguera, N., Song, M., Divona, M. et al. Nucleophosmin/B26 regulates PTEN through interaction with HAUSP in acute myeloid leukemia. Leukemia 27, 1037–1043 (2013). https://doi.org/10.1038/leu.2012.314

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