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Oncogene. 2018 Jan 4;37(1):95-106. doi: 10.1038/onc.2017.282. Epub 2017 Sep 11.

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

Author information

1
Molecular, Cellular and Developmental Biology Graduate Program and The Center for RNA Biology, The Ohio State University, Columbus, OH, USA.
2
Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
3
Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA.
4
Takeda California, Inc., Drug Safety Research & Evaluation 10410 Science Center Drive, San Diego, CA 92121, USA.
5
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.

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.

PMID:
28892044
PMCID:
PMC5756115
DOI:
10.1038/onc.2017.282
[Indexed for MEDLINE]
Free PMC Article

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