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Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia

Nature Immunology volume 11, pages 717–724 (2010)Cite this article

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An Erratum to this article was published on 01 October 2010

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Abstract

ZFP36L1 and ZFP36L2 are RNA-binding proteins (RBPs) that interact with AU-rich elements in the 3′ untranslated region of mRNA, which leads to mRNA degradation and translational repression. Here we show that mice that lacked ZFP36L1 and ZFP36L2 during thymopoiesis developed a T cell acute lymphoblastic leukemia (T-ALL) dependent on the oncogenic transcription factor Notch1. Before the onset of T-ALL, thymic development was perturbed, with accumulation of cells that had passed through the β-selection checkpoint without first expressing the T cell antigen receptor β-chain (TCRβ). Notch1 expression was higher in untransformed thymocytes in the absence of ZFP36L1 and ZFP36L2. Both RBPs interacted with evolutionarily conserved AU-rich elements in the 3′ untranslated region of Notch1 and suppressed its expression. Our data establish a role for ZFP36L1 and ZFP36L2 during thymocyte development and in the prevention of malignant transformation.

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Figure 1: Development of T-ALL in dKO mice.
Figure 2: Thymocyte development is perturbed before tumor development.
Figure 3: Higher Notch1 expression in dKO mice.
Figure 4: ZFP36L1 and ZFP36L2 exert suppression via interaction with sequences in the Notch1 3′ UTR.
Figure 5: Inhibition of Notch or reexpression of ZFP36L1 is toxic to tumor growth.

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  • 22 July 2010

    In the version of this article initially published, two labels in the key in Figure 1a are reversed. The correct labels are dKO (red line) and Control (blue line). The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank A. Clark (Kennedy Institute of Rheumatology, London) for the pcDNA3.myc.WT ZFP36L1 expression construct and pFLAG.CMV2-ZFP36L2; and J. Zuniga-Pflucker (University of Toronto) for OP9-DL1 stromal cells. Supported by Cancer Research UK (D.J.H.), the Addenbrooke's Charitable Trust (D.J.H.), the Medical Research Council (M.T., and a Collaborative Award in Science and Engineering to A.G.), the Biotechnology and Biological Sciences Research Council (BB/C506121/1 to M.T.), the US National Institutes of Health (R01CA120196 and R01CA129382 to A.A.F.), the European College of Obstetrics and Gynaecology tumor bank (U24 CA114737), the Leukemia & Lymphoma Society (A.A.F.), Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (K.D.K.) and the Belgian American Educational Foundation (K.D.K.).

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Authors and Affiliations

  1. Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK

    Daniel J Hodson, Michelle L Janas, Alison Galloway, Sarah E Bell, Cheuk M Li & Martin Turner

  2. Bioinformatics Group, The Babraham Institute, Cambridge, UK

    Simon Andrews

  3. Medical Research Council Laboratory of Molecular Biology, Cambridge, UK

    Richard Pannell

  4. Department of Molecular Biology, Genentech, South San Francisco, California, USA

    Christian W Siebel

  5. Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland

    H Robson MacDonald

  6. Institute for Cancer Genetics, Columbia University Medical Centre, New York, New York, USA

    Kim De Keersmaecker & Adolfo A Ferrando

  7. Department of Pathology, Columbia University Medical Centre, New York, New York, USA

    Adolfo A Ferrando

  8. Department of Pediatrics, Columbia University Medical Centre, New York, New York, USA

    Adolfo A Ferrando

  9. Institute of Medical Immunology, Charité-Universitätsmedizin, Campus Mitte, Berlin, Germany

    Gerald Grutz

  10. Center for Biomaterial Development, Institute of Polymer Research, GKSS, Teltow, Germany

    Gerald Grutz

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Contributions

D.J.H. designed and did experiments, analyzed data and wrote the paper; M.L.J., A.G. and S.E.B. designed and did experiments; C.M.L., R.P., G.G., C.W.S. and H.R.M. developed analytical tools; S.A. designed experiments and analyzed data; K.D.M. and A.A.F. analyzed data; and M.T. designed experiments, analyzed data and wrote the paper.

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Correspondence to Martin Turner.

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Hodson, D., Janas, M., Galloway, A. et al. Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia. Nat Immunol 11, 717–724 (2010). https://doi.org/10.1038/ni.1901

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