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Animal Models

Induction of the 5S RNP–Mdm2–p53 ribosomal stress pathway delays the initiation but fails to eradicate established murine acute myeloid leukemia

Leukemia volume 31, pages 213–221 (2017)Cite this article

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Abstract

Mutations resulting in constitutive activation of signaling pathways that regulate ribosome biogenesis are among the most common genetic events in acute myeloid leukemia (AML). However, whether ribosome biogenesis presents as a therapeutic target to treat AML remains unexplored. Perturbations in ribosome biogenesis trigger the 5S ribonucleoprotein particle (RNP)–Mdm2–p53 ribosomal stress pathway, and induction of this pathway has been shown to have therapeutic efficacy in Myc-driven lymphoma. In the current study we address the physiological and therapeutic role of the 5S RNP–Mdm2–p53 pathway in AML. By utilizing mice that have defective ribosome biogenesis due to downregulation of ribosomal protein S19 (Rps19), we demonstrate that induction of the 5S RNP–Mdm2–p53 pathway significantly delays the initiation of AML. However, even a severe Rps19 deficiency that normally results in acute bone marrow failure has no consistent efficacy on already established disease. Finally, by using mice that harbor a mutation in the Mdm2 gene disrupting its binding to 5S RNP, we show that loss of the 5S RNP–Mdm2–p53 pathway is dispensable for development of AML. Our study suggests that induction of the 5S RNP–Mdm2–p53 ribosomal stress pathway holds limited potential as a single-agent therapy in the treatment of AML.

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Acknowledgements

We thank Dr Guy Sauvageau (Université de Montréal) for kindly providing the MSCV-Hoxa9-Meis1 vector. We thank Shamit Soneji (Lund University) for the bioinformatic support. This work was supported by The Swedish Children’s Cancer Society (to PJ), The Crafoord Foundation (to PJ), The Gunnar Nilsson Cancer Foundation (to DB and PJ), The Swedish Research Council (to DB and MSL), the Swedish Cancer Society (to DB) and ERC Consolidator grant 615068 (to DB).

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Authors and Affiliations

  1. Division of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden

    P Jaako, A Ugale, M Wahlestedt, T Velasco-Hernandez & D Bryder

  2. Department of Hematology, Linköping University Hospital, Linköping, Sweden

    J Cammenga

  3. Department of Medical Biochemistry and Biophysics, SciLifeLab, Karolinska Institute, Stockholm, Sweden

    M S Lindström

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  1. P Jaako
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  2. A Ugale
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Correspondence to D Bryder.

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Jaako, P., Ugale, A., Wahlestedt, M. et al. Induction of the 5S RNP–Mdm2–p53 ribosomal stress pathway delays the initiation but fails to eradicate established murine acute myeloid leukemia. Leukemia 31, 213–221 (2017). https://doi.org/10.1038/leu.2016.159

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