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JAK2V617F negatively regulates p53 stabilization by enhancing MDM2 via La expression in myeloproliferative neoplasms

Oncogene volume 31, pages 1323–1333 (2012)Cite this article

Abstract

JAK2V617F is a gain of function mutation that promotes cytokine-independent growth of myeloid cells and accounts for a majority of myeloproliferative neoplasms (MPN). Mutations in p53 are rarely found in these diseases before acute leukemia transformation, but this does not rule out a role for p53 deregulation in disease progression. Using Ba/F3-EPOR cells and ex vivo cultured CD34+ cells from MPN patients, we demonstrate that expression of JAK2V617F affected the p53 response to DNA damage. We show that E3 ubiquitin ligase MDM2 accumulated in these cells, due to an increased translation of MDM2 mRNA. Accumulation of the La autoantigen, which interacts with MDM2 mRNA and promotes its translation, was responsible for the increase in MDM2 protein level and the subsequent degradation of p53 after DNA damage. Downregulation of La protein or cell treatment with nutlin-3, a MDM2 antagonist, restored the p53 response to DNA damage and the cytokine-dependence of Ba/F3-EPOR-JAK2V617F cells. Altogether, these data indicate that the JAK2V617F mutation affects p53 response to DNA damage through the upregulation of La antigen and accumulation of MDM2. They also suggest that p53 functional inactivation accounts for the cytokine hypersensitivity of JAK2V617F MPN and might have a role in disease progression.

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Acknowledgements

We thank all the patients and the controls who participated in the study, and AstraZeneca for the gift of the JAK2 inhibitor (AZD1480). We are grateful to Drs LT Vassilev and R Fahraeus for fruitful discussion. We also thank Dr F Wendling for critical reading of the manuscript. This work was supported by grants from the Ligue Nationale Contre le Cancer (équipe labellisée 2007–2010 et 2010–2012), INCa (projets libres 2007) and INSERM. IP was a recipient from INCA, MN from the Ligue Nationale Contre le Cancer, BMM from the Fondation pour la Recherche Médicale.

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Authors and Affiliations

  1. INSERM UMR 1009, Villejuif, France

    M Nakatake, B Monte-Mor, N Debili, N Casadevall, V Ribrag, E Solary, W Vainchenker & I Plo

  2. Université Paris XI, UMR1009, Institut Gustave Roussy, Villejuif, France

    M Nakatake, B Monte-Mor, N Debili, V Ribrag, E Solary, W Vainchenker & I Plo

  3. Institut Gustave Roussy, Villejuif, France

    M Nakatake, B Monte-Mor, N Debili, V Ribrag, E Solary, W Vainchenker & I Plo

  4. AP-HP, Laboratoire d’hématologie-Hôpital Saint Antoine, Paris, France

    N Casadevall

  5. Université Pierre et Marie Curie, Paris VI, France

    N Casadevall

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  1. M Nakatake
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Nakatake, M., Monte-Mor, B., Debili, N. et al. JAK2V617F negatively regulates p53 stabilization by enhancing MDM2 via La expression in myeloproliferative neoplasms. Oncogene 31, 1323–1333 (2012). https://doi.org/10.1038/onc.2011.313

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