title: Germline Mutations in Mtap Cooperate with Myc to Accelerate Tumorigenesis in Mice.
abstract: 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(+/-) .
  
  
  
  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.
  
  
  
  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.
  
  
  
  Our findings show that germline inactivation of a single Mtap allele alters gene expression and enhances lymphomagenesis in Eµ-myc mice.
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, Unites States of America.
authors.forename: Yuwaraj
authors.initials: Y
authors.lastname: Kadariya
authors.forename: Baiqing
authors.initials: B
authors.lastname: Tang
authors.forename: Liqun
authors.initials: L
authors.lastname: Wang
authors.forename: Tahseen
authors.initials: T
authors.lastname: Al-Saleem
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Slifker
authors.forename: Warren D
authors.initials: WD
authors.lastname: Kruger
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology*; D018095:Germ-Line Mutation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D015996:Survival Rate; D059467:Transcriptome
chemical_list: C490547:MAP1A protein, mouse; D008869:Microtubule-Associated Proteins; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse