Regulation of the Arf tumor suppressor in Eμ-Myc transgenic mice: longitudinal study of Myc-induced lymphomagenesis

Abstract

Abstract Lymphomagenesis in Eμ-Myc mice is opposed by the Arf tumor suppressor, whose inactivation compromises p53 function and accelerates disease. Finding nascent Eμ-Myc–induced tumors in which p19Arf causes cell-cycle arrest or apoptosis is problematic, since such cells will be eliminated until Arf or p53 function is lost. Knock-in mice expressing a green fluorescent protein (GFP) in lieu of Arf coding sequences allow analysis of Arfpromoter regulation uncoupled from p19Arf action. Prior to frank lymphoma development, unexpectedly low levels of Eμ-Myc–induced p19Arf or GFP were expressed. However, as lymphomas arose in Arf+/GFP heterozygotes, additional oncogenic events synergized with Eμ-Myc to further induce the functionally null Arf-Gfp allele. Concomitant up-regulation of p19Arf was not observed; instead, the wild-type allele was inactivated. We infer that very low levels of Arf are tumor suppressive, and that further induction provides the selective pressure for the emergence of tumors that have inactivated the gene.