PROVIRAL TAGGING IN E-MU-MYC TRANSGENIC MICE LACKING THE PIM-1 PROTOONCOGENE LEADS TO COMPENSATORY ACTIVATION OF PIM-2

The Pim-1 proto-oncogene is one of the most potent collaborators of th e myc proto-oncogenes in inducing lymphomagenesis in mice, Contrary to the profound effects when overexpressed in vivo, Pim-1-deficient mice showed only subtle phenotypic alterations, which could indicate the p resence of redundantly acting genes, In line with this, a PCR-based sc reen has led to the identification of a closely homologous gene, Pim-2 , The X-linked Pim-2 gene is 53% identical to Pim-1 at the amino acid level and shares substrate preference and the usage of non-AUG initiat ion codons with Pim-1, We have used these data to test whether the str ong synergistic interaction between Pim-1 and c-myc can be utilized to gain access to Pim-1 compensatory pathways. We reasoned that, upon pr oviral tagging in compound mutant mice (E mu-myc/Pim-1(-/-) mice), the selective advantage of cells carrying provirally activated genes, tha t act downstream from or parallel to Pim-1, would increase. We show he re that this is the case. A dramatic increase (from 15 to 80%) was fou nd in the frequency of proviral activation of the Pim-2 gene, These da ta show that the described strategy of 'complementation tagging' repre sents a powerful new tool to identify components of pathways involved in processes as complex as multistep tumorigenesis.