Mouse modeling provides insights into Daxx and Atrx tumor suppressive mechanisms in the endocrine pancreas.

Genome sequencing has revealed the importance of epigenetic regulators in tumorigenesis. The genes encoding the chromatin remodeling complex DAXX:ATRX are frequently mutated in pancreatic neuroendocrine tumors (PanNETs); however, the underlying mechanisms of how mutations contribute to tumorigenesis are only partially understood, in part because of the lack of relevant pre-clinical models. Here we used genetically engineered mouse models combined with environmental stress to evaluate the tumor suppressor functions of Daxx and Atrx in the mouse pancreas. Daxx or Atrx loss, alone or in combination with Men1 loss, do not drive nor accelerate pancreatic neuroendocrine tumorigenesis. Moreover, Daxx loss does not cooperate with environmental stresses (ionizing radiation or pancreatitis) or with the loss of other tumor suppressors (Pten or p53) to promote pancreatic neuroendocrine tumorigenesis. However, due to promiscuity of the Cre promoter used, hepatocellular carcinomas (HCC) and osteosarcomas were observed in some instances. Overall, our findings suggest that Daxx and Atrx are not robust tumor suppressors in the endocrine pancreas of mice and indicate the context of a human genome is essential for tumorigenesis.