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Here, we report that Dino, a lncRNA required for p53 signaling, suppresses spontaneous tumorigenesis in mice. <i>Dino^−/−</i> mice develop significantly more malignant tumors than <i>Dino^+/+</i> littermate controls, consisting predominantly of sarcomas, B cell lymphomas and additional rare tumors. While the prevalence of lymphomas and sarcomas in <i>Dino^−/−</i> mice is similar to that of mice with p53 loss, important distinctions emerged. <i>p53</i>-null mice predominantly develop T cell lymphomas; however, no spontaneous T cell lymphoma was observed in <i>Dino^−/−</i> mice. Rather than being a phenocopy of the <i>p53</i>-null tumor spectrum, spontaneous tumors in <i>Dino^−/−</i> mice resemble the spectrum of human cancers in which <i>DINO</i> is recurrently silenced by methylation in a manner that is mutually exclusive with <i>TP53</i> alterations, suggesting that similar tissues in human and mouse require <i>DINO</i> for tumor suppression. Consistent with a tissue-specific role for Dino in tumor suppression, loss of <i>Dino</i> 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.