Context matters - Daxx and Atrx are not robust tumor suppressors in the murine endocrine pancreas

Chang Sun, Jeannelyn S. Estrella, Elizabeth M. Whitley, Gilda P. Chau, Guillermina Lozano, Amanda R. Wasylishen

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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; however, the underlying mechanisms of how mutations contribute to tumorigenesis are only partially understood, in part because of the lack of relevant preclinical 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, did not drive or accelerate pancreatic neuroendocrine tumorigenesis. Moreover, Daxx loss did 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, owing to promiscuity of the Cre promoter used, hepatocellular carcinomas 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 that the context of a human genome is essential for tumorigenesis. This article has an associated First Person interview with the first author of the paper.

Original languageEnglish (US)
Article numberdmm049552
JournalDMM Disease Models and Mechanisms
Volume15
Issue number8
DOIs
StatePublished - Aug 2022

Keywords

  • Atrx
  • Daxx
  • Men1
  • Mouse model
  • Pancreatic neuroendocrine tumor

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • General Biochemistry, Genetics and Molecular Biology

MD Anderson CCSG core facilities

  • Research Animal Support Facility
  • Advanced Technology Genomics Core
  • Genetically Engineered Mouse Facility

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