Abstract 4140: The dual role of MDM2-ALT1 as both a suppressor and driver of oncogenesis is highlighted in a new RMS mouse model
Authors: Daniel F. Comiskey, Aishwarya G. Jacob, Matias Montes, Krista La Perle, Prosper N. Boyaka, Dawn S. Chandler
Journal: Cancer Research (2018)

Abstract MDM2 is an important negative regulator of protein stability and transcriptional activity of tumor suppressor p53. We have previously shown that the alternatively spliced variant of MDM2, MDM2-ALT1, is induced specifically after exposure to ultraviolet light (UVC) and cisplatin treatment and is associated with various soft tissue sarcomas, including rhabdomyosarcoma (RMS). We have also shown that MDM2-ALT1 interferes with the normal heterodimer formation between MDM2 and MDM4 that is required for efficient p53 degradation by MDM2-mediated ubiquitination. Consistently, we have shown upregulation of p53 activity as a result of transient transfection of this isoform in wild-type p53 background cells. Furthermore, we observed increased levels of p53 and its downstream targets, p21 and Bax, when MDM2-ALT1 is expressed in cells, as well as the expected cell-cycle arrest. In contrast, we have also shown the MDM2-ALT1 can promote cell proliferation and metastatic behavior when transfected into tumor cells lacking an intact p53 pathway. These seemingly opposing roles of MDM2-ALT1 are poorly characterized in vivo, and models to better understand them are not available. To investigate the effects of MDM2-ALT1 on cell cycle and the progression of tumorigenesis in the context of the whole animal, we generated an inducible MDM2-ALT1 mouse model. When MDM2-ALT1 is ubiquitously expressed in mice lacking p53 expression, we see an increased incidence of spindle cell sarcomas, including RMS. Hence, constitutive MDM2-ALT1 expression is oncogenic and exacerbates the tumorigenesis induced by p53 loss. We next assessed the role of MDM2-ALT1 in the presence of wild-type p53. Surprisingly, when MDM2-ALT1 expression was limited to B cells in the presence of wild-type p53 expression, it also gave rise to increased tumorigenesis, albeit with an extended latency (after 18 months). Interestingly, flow cytometric analyses for B-cell markers prior to the onset of tumorigenesis 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 a p53-dependent response to persistent MDM2-ALT1 expression. In conclusion, the MDM2 ALT1 splice variant is a modifier of both p53-dependent and p53-independent tumorigenesis in vivo. Our findings underscore the importance of MDM2 post-transcriptional regulation in controlling the p53 pathway and in tumorigenesis. Furthermore, the MDM2-ALT1-expressing p53 null mice represent a novel mouse model of fusion-negative RMS, a cancer type with few animal models available for therapy design and testing. Citation Format: Daniel F. Comiskey, Aishwarya G. Jacob, Matias Montes, Krista La Perle, Prosper N. Boyaka, Dawn S. Chandler. The dual role of MDM2-ALT1 as both a suppressor and driver of oncogenesis is highlighted in a new RMS mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4140.