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Molecular Targets for Therapy

Notch3-mediated regulation of MKP-1 levels promotes survival of T acute lymphoblastic leukemia cells

Leukemia volume 25, pages 588–598 (2011)Cite this article

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Abstract

Activation of the Notch pathway occurs commonly in T acute lymphoblastic leukemia (T-ALL) because of mutations in Notch1 or Fbw7 and is involved in the regulation of cell proliferation and survival. Deregulated Notch3 signalling has also been shown to promote leukemogenesis in transgenic mice, but the targets of Notch3 in human T-ALL cells remain poorly characterized. Here, we show that Notch3 controls levels of mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1). In a model of T-ALL cell dormancy, both Notch3 activation and MKP-1 expression were upregulated in aggressive compared with dormant tumors, and this inversely correlated with the levels of phosphorylated p38 and extracellular signal-regulated kinase1/2 (ERK1/2) MAPKs, two canonical MKP-1 targets. We demonstrate that MKP-1 protein levels are regulated by Notch3 in T-ALL cell lines because its silencing by RNA interference or treatment with γ-secretase inhibitors induced strong MKP-1 reduction whereas activation of Notch3 signalling had the opposite effect. Furthermore, MKP-1 has an important role in T-ALL cell survival because its attenuation by short hairpin RNA significantly increased cell death under stress conditions. This protective function has a key role in vivo, as MKP-1-deficient cells showed impaired tumorigenicity. These results elucidate a novel mechanism downstream of Notch3 that controls the survival of T-ALL cells.

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Acknowledgements

We are grateful to Annunciata Vecchi (Mario Negri Institute) for providing SIEC, Adolfo Ferrando (Columbia University) for providing T-ALL cell lines, Minhong Yan (Genentech) for the YW152F mAb, Micol Silic-Benussi (University of Padova) for technical help with some experiments. This work was supported in part by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC) and Fondazione Italiana per la Ricerca sul Cancro (FIRC); Ministry of University and Research, 60% and PRIN; Ministry of Health, Oncology Program 2006 and Ricerca Finalizzata 2007; Banca Popolare di Verona; Foundation CARIPARO Projects of Excellence Program 2008.

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Author notes

  1. M Masiero and S Minuzzo: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology and Surgical Sciences, University of Padova, Padova, Italy

    M Masiero, S Minuzzo, L Moserle, L Persano, V Agnusdei & A Amadori

  2. Istituto Oncologico Veneto—IRCCS, Padova, Italy

    I Pusceddu, A Amadori & S Indraccolo

  3. Institute for Cancer Genetics, Columbia University, New York, NY, USA

    V Tosello

  4. Department of Pediatrics, Oncohematology Laboratory, University of Padova, Padova, Italy

    G Basso

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  1. M Masiero
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Correspondence to S Indraccolo.

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Masiero, M., Minuzzo, S., Pusceddu, I. et al. Notch3-mediated regulation of MKP-1 levels promotes survival of T acute lymphoblastic leukemia cells. Leukemia 25, 588–598 (2011). https://doi.org/10.1038/leu.2010.323

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