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Molecular targets for therapy

Disruption of the 5S RNP–Mdm2 interaction significantly improves the erythroid defect in a mouse model for Diamond-Blackfan anemia

Leukemia volume 29, pages 2221–2229 (2015)Cite this article

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Abstract

Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by haploinsufficiency of genes encoding ribosomal proteins (RPs). Perturbed ribosome biogenesis in DBA has been shown to induce a p53-mediated ribosomal stress response. However, the mechanisms of p53 activation and its relevance for the erythroid defect remain elusive. Previous studies have indicated that activation of p53 is caused by the inhibition of mouse double minute 2 (Mdm2), the main negative regulator of p53, by the 5S ribonucleoprotein particle (RNP). Meanwhile, it is not clear whether this mechanism solely mediates the p53-dependent component found in DBA. To approach this question, we crossed our mouse model for RPS19-deficient DBA with Mdm2C305F knock-in mice that have a disrupted 5S RNP–Mdm2 interaction. Upon induction of the Rps19 deficiency, Mdm2C305F reversed the p53 response and improved expansion of hematopoietic progenitors in vitro, and ameliorated the anemia in vivo. Unexpectedly, disruption of the 5S RNP–Mdm2 interaction also led to selective defect in erythropoiesis. Our findings highlight the sensitivity of erythroid progenitor cells to aberrations in p53 homeostasis mediated by the 5S RNP–Mdm2 interaction. Finally, we provide evidence indicating that physiological activation of the 5S RNP-Mdm2-p53 pathway may contribute to functional decline of the hematopoietic system in a cell-autonomous manner over time.

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Acknowledgements

This work was supported by The Swedish Children’s Cancer Society (PJ, SK), The Crafoord Foundation (PJ), The Gunnar Nilsson Cancer Foundation (DB, PJ), The Swedish Research Council (MSL, SK), The Swedish Cancer Society (SK), Hemato-Linné grant (Swedish Research Council Linnaeus), The Tobias Prize awarded by The Royal Swedish Academy of Sciences financed by The Tobias Foundation (SK) and the EU project grants STEMEXPAND and PERSIST (SK).

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Authors and Affiliations

  1. Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden

    P Jaako, S Debnath, K Olsson, J Flygare & S Karlsson

  2. Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden

    P Jaako & D Bryder

  3. Department of Radiation Oncology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Y Zhang

  4. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

    M S Lindström

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  1. P Jaako
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Correspondence to S Karlsson.

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Jaako, P., Debnath, S., Olsson, K. et al. Disruption of the 5S RNP–Mdm2 interaction significantly improves the erythroid defect in a mouse model for Diamond-Blackfan anemia. Leukemia 29, 2221–2229 (2015). https://doi.org/10.1038/leu.2015.128

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