The oncogenic Runx3–Myc axis defines<i>p53</i>-deficient osteosarcomagenesis

<jats:title>Abstract</jats:title><jats:p>Osteosarcoma (OS) in human patients is characterized by genetic alteration of<jats:italic>TP53</jats:italic>. Osteoprogenitor-specific<jats:italic>p53</jats:italic>-deleted mice (<jats:italic>OS</jats:italic>mice) have been widely used to study the process of osteosarcomagenesis. However, the molecular mechanisms responsible for the development of OS upon p53 inactivation remain largely unknown. In this study, we detected prominent RUNX3/Runx3 expression in human and mouse<jats:italic>p53</jats:italic>-deficient OS. Myc was aberrantly upregulated by Runx3 via mR1, a consensus Runx site in the<jats:italic>Myc</jats:italic>promoter, in a manner dependent on<jats:italic>p53</jats:italic>deficiency. Reduction of the Myc level by disruption of mR1 or Runx3 knockdown decreased the tumorigenicity of<jats:italic>p53-</jats:italic>deficient OS cells and effectively suppressed OS development in<jats:italic>OS</jats:italic>mice. Furthermore, Runx inhibitors exerted therapeutic effects on<jats:italic>OS</jats:italic>mice. Together, these results show that<jats:italic>p53</jats:italic>deficiency promotes osteosarcomagenesis in human and mouse by allowing Runx3 to induce oncogenic Myc expression.</jats:p>