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A novel mouse model of rhabdomyosarcoma underscores the dichotomy of MDM2-ALT1 function in vivo

Oncogene volume 37, pages 95–106 (2018)Cite this article

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Abstract

Alternative splicing of the oncogene murine double minute 2 (MDM2) is induced in response to genotoxic stress. MDM2-ALT1, the major splice variant generated, is known to activate the p53 pathway and impede full-length MDM2’s negative regulation of p53. Despite this perceptible tumor-suppressive role, MDM2-ALT1 is also associated with several cancers. Furthermore, expression of MDM2-ALT1 has been observed in aggressive metastatic disease in pediatric rhabdomyosarcoma (RMS), irrespective of histological subtype. Therefore, we generated a transgenic MDM2-ALT1 mouse model that would allow us to investigate the effects of this splice variant on the progression of tumorigenesis. Here we show that when MDM2-ALT1 is ubiquitously expressed in p53 null mice it leads to increased incidence of spindle cell sarcomas, including RMS. Our data provide evidence that constitutive MDM2-ALT1 expression is itself an oncogenic lesion that aggravates the tumorigenesis induced by p53 loss. On the contrary, when MDM2-ALT1 is expressed solely in B-cells in the presence of homozygous wild-type p53 it leads to significantly increased lymphomagenesis (56%) when compared with control mice (27%). However, this phenotype is observable only at later stages in life (⩾18 months). Moreover, flow cytometric analyses for B-cell markers revealed an MDM2-ALT1-associated decrease in the B-cell population of the spleens of these animals. Our data suggest that the B-cell loss is p53 dependent and is a response mounted to persistent MDM2-ALT1 expression in a wild-type p53 background. Overall, our findings highlight the importance of an MDM2 splice variant as a critical modifier of both p53-dependent and -independent tumorigenesis, underscoring the complexity of MDM2 posttranscriptional regulation in cancer. Furthermore, MDM2-ALT1-expressing p53 null mice represent a novel mouse model of fusion-negative RMS.

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Acknowledgements

We thank Matthew Rouhier for optimizing conditions for cell cycle analysis of B-cells; Juliann Rectenwald and The Ohio State University Comparative Pathology & Mouse Phenotyping Shared Resource, supported in part through NCI Cancer Center Support Grant P30 CA016058; and funding sources Alex’s Lemonade Stand, Sarcoma Foundation of America, NIH (CA133571) awarded to DSC and Pelotonia (awarded to DFC and AGJ). We also thank Dr Andras Nagy for kindly providing the plasmid used in generating the mouse models.

Author information

Author notes

  1. D F Comiskey Jr and A G Jacob: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular, Cellular and Developmental Biology Graduate Program and The Center for RNA Biology, The Ohio State University, Columbus, OH, USA

    D F Comiskey Jr, A G Jacob, M Montes, A S Tapia-Santos, T W Bebee & D S Chandler

  2. Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA

    D F Comiskey Jr, A G Jacob, B L Sanford, M Montes, A K Goodwin, E Matsa, A S Tapia-Santos, T W Bebee & D S Chandler

  3. Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA

    H Steiner, J Grieves, K La Perle & P Boyaka

  4. Takeda California, Inc., Drug Safety Research & Evaluation 10410 Science Center Drive, San Diego, CA 92121, USA,

    J Grieves

  5. Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA

    D S Chandler

Authors
  1. D F Comiskey Jr
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  2. A G Jacob
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  3. B L Sanford
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  4. M Montes
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  5. A K Goodwin
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  6. H Steiner
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  7. E Matsa
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  8. A S Tapia-Santos
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  9. T W Bebee
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  10. J Grieves
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  11. K La Perle
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  12. P Boyaka
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  13. D S Chandler
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Corresponding author

Correspondence to D S Chandler.

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The authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Oncogene website

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Comiskey Jr, D., Jacob, A., Sanford, B. et al. A novel mouse model of rhabdomyosarcoma underscores the dichotomy of MDM2-ALT1 function in vivo. Oncogene 37, 95–106 (2018). https://doi.org/10.1038/onc.2017.282

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  • DOI: https://doi.org/10.1038/onc.2017.282

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