Germline Mutations in Mtap Cooperate with Myc to Accelerate Tumorigenesis in Mice

Objective:The gene encoding the methionine salvage pathway methylthioadenosine phosphorylase (MTAP) is a tumor suppressor gene that is frequently inactivated in a wide variety of human cancers. In this study, we have examined if heterozygosity for a null mutation in Mtap (Mtap^lacZ) could accelerate tumorigenesis development in two different mouse cancer models, Eμ-myc transgenic and Pten^+/-.Methods:Mtap Eμ-myc and Mtap Pten mice were generated and tumor-free survival was monitored over time. Tumors were also examined for a variety of histological and protein markers. In addition, microarray analysis was performed on the livers of Mtap^lacZ/+ and Mtap^+/+ mice.Results:Survival in both models was significantly decreased in Mtap^lacZ/+ compared to Mtap^+/+ mice. In Eμ-myc mice, Mtap mutations accelerated the formation of lymphomas from cells in the early pre-B stage, and these tumors tended to be of higher grade and have higher expression levels of ornithine decarboxylase compared to those observed in control Eμ-myc Mtap^+/+ mice. Surprisingly, examination of Mtap status in lymphomas in Eμ-myc Mtap^lacZ/+ and Eμ-myc Mtap^+/+ animals did not reveal significant differences in the frequency of loss of Mtap protein expression, despite having shorter latency times, suggesting that haploinsufficiency of Mtap may be playing a direct role in accelerating tumorigenesis. Consistent with this idea, microarray analysis on liver tissue from age and sex matched Mtap^+/+ and Mtap^lacZ/+ animals found 363 transcripts whose expression changed at least 1.5-fold (P<0.01). Functional categorization of these genes reveals enrichments in several pathways involved in growth control and cancer.Conclusion:Our findings show that germline inactivation of a single Mtap allele alters gene expression and enhances lymphomagenesis in Eμ-myc mice.