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β-Catenin Expression Results in p53-Independent DNA Damage and Oncogene-Induced Senescence in Prelymphomagenic Thymocytes In Vivo ^,

Lymphocyte Development Unit, Laboratory of Immunology,¹ Laboratory of Cellular and Molecular Biology, National Institute on Aging, Baltimore, Maryland 21224,² Section of Cancer Genomics, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892³

Received 28 August 2008/ Returned for modification 22 October 2007/ Accepted 11 December 2007

The expression of β-catenin, a potent oncogene, is causally linked to tumorigenesis. Therefore, it was surprising that the transgenic expression of oncogenic β-catenin in thymocytes resulted in thymic involution instead of lymphomagenesis. In this report, we demonstrate that this is because the expression of oncogenic β-catenin induces DNA damage, growth arrest, oncogene-induced senescence (OIS), and apoptosis of immature thymocytes. In p53-deficient mice, the expression of oncogenic β-catenin still results in DNA damage and OIS, but the thymocytes survive and eventually progress to thymic lymphoma. β-Catenin-induced thymic lymphomas are distinct from lymphomas that arise in p53^–/– mice. They are CD4^– CD8^–, while p53-dependent lymphomas are largely CD4⁺ CD8⁺, and they develop at an earlier age and in the absence of c-Myc expression or Notch1 signaling. Thus, we report that oncogenic β-catenin-induced, p53-independent growth arrest and OIS and p53-dependent apoptosis protect developing thymocytes from transformation by oncogenic β-catenin.

Published ahead of print on 26 December 2007.

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