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

PLoS One. 2013 Jun 26;8(6):e67635. doi: 10.1371/journal.pone.0067635. Print 2013.


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.

MeSH terms

  • Animals
  • Carcinogenesis / genetics*
  • Carcinogenesis / pathology*
  • Germ-Line Mutation*
  • Humans
  • Mice
  • Mice, Transgenic
  • Microtubule-Associated Proteins / physiology*
  • PTEN Phosphohydrolase / physiology*
  • Proto-Oncogene Proteins c-myc / physiology*
  • Survival Rate
  • Transcriptome


  • MAP1A protein, mouse
  • Microtubule-Associated Proteins
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • PTEN Phosphohydrolase
  • Pten protein, mouse