Abstract
ObjectiveThe 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 (MtaplacZ) 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 MtaplacZ/+ and Mtap+/+ mice.ResultsSurvival in both models was significantly decreased in MtaplacZ/+ 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 MtaplacZ/+ 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 MtaplacZ/+ 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.ConclusionOur findings show that germline inactivation of a single Mtap allele alters gene expression and enhances lymphomagenesis in Eµ-myc mice.
Highlights
methylthioadenosine phosphorylase (MTAP) is a metabolic enzyme in the methionine salvage pathway that converts the polyamine synthesis byproduct 59dideoxy-59-methylthioadenosine (MTA) into adenine and methylthioribose-1-phosphate and is expressed in all tissues throughout the body [1,2]
MtaplacZ/+ Decreases Survival in Em-myc and Pten+/2 Mice Homozygous deletion of MTAP gene (Mtap) leads to early embryonic lethality
MtaplacZ/+ mice are entirely normal until about 18 months of age when they will start to succumb to T-cell lymphoma
Summary
MTAP is a metabolic enzyme in the methionine salvage pathway that converts the polyamine synthesis byproduct 59dideoxy-59-methylthioadenosine (MTA) into adenine and methylthioribose-1-phosphate and is expressed in all tissues throughout the body [1,2]. Similar deletions occur in the same gene cluster that is located on chromosome 4 [17,18,19] Since these deletions generally inactivate CDKN2A/ARF as well as MTAP, it was initially hypothesized that loss of MTAP in tumors was due to it being a co-incident bystander. It was recently reported that humans with germline MTAP mutations have Diaphyseal medullary stenosis with malignant fibrous histiocytoma, an autosomal-dominant syndrome characterized by bone dysplasia, myopathy, and bone cancer [24]. Taken together, these observations suggest that MTAP functions as a tumor suppressor gene independent of CDKN2A/ARF
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