A Unique Spectrum of Spontaneous Tumors in Dino Knockout Mice Identifies Tissue-Specific Requirements for Tumor Suppression

Abstract

Here, we report that Dino, a lncRNA required for p53 signaling, suppresses spontaneous tumorigenesis in mice. Dino−/− mice develop significantly more malignant tumors than Dino+/+ littermate controls, consisting predominantly of sarcomas, B cell lymphomas and additional rare tumors. While the prevalence of lymphomas and sarcomas in Dino−/− mice is similar to that of mice with p53 loss, important distinctions emerged. p53-null mice predominantly develop T cell lymphomas; however, no spontaneous T cell lymphoma was observed in Dino−/− mice. Rather than being a phenocopy of the p53-null tumor spectrum, spontaneous tumors in Dino−/− mice resemble the spectrum of human cancers in which DINO is recurrently silenced by methylation in a manner that is mutually exclusive with TP53 alterations, suggesting that similar tissues in human and mouse require DINO for tumor suppression. Consistent with a tissue-specific role for Dino in tumor suppression, loss of Dino had no impact on the development of radiation-induced T cell lymphoma and oncogene-driven medulloblastoma, tumors that are accelerated by the loss of p53. Taken together, these data indicate that Dino serves as a potent tumor suppressor molecule specific to a select subset of tissues in mice and humans.