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

Abstract

Alternative splicing of the oncogene 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 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 to 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 p53-independent tumorigenesis, underscoring the complexity of MDM2 post-transcriptional regulation in cancer. Furthermore, MDM2-ALT1-expressing p53 null mice represent a novel mouse model of fusion-negative RMS.