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

Lymphomagenesis in E mu-Myc mice is opposed by the Arf tumor suppressor, whose inactivation compromises p53 function and accelerates disease. Finding nascent E mu-Myc-induced tumors in which p19(Arf) 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 Arf promoter regulation uncoupled from p19(Arf) action. Prior to frank lymphoma development, unexpectedly low levels of E mu-Myc-induced p19(Arf) or GFP were expressed. However, as lymphomas arose in Arf(+/GFP) heterozygotes, additional oncogenic events synergized with E mu-Myc to further induce the functionally null Arf-Gfp allele. Concomitant up-regulation of p19(Arf) 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. (c) 2007 by The American Society of Hematology