Transgenic expression of human MGMT blocks the hypersensitivity of PMS2-deficient mice to low dose MNU thymic lymphomagenesis

Mice deficient in the DNA mismatch repair (MMR) gene, PMS2, develop spontan eous thymic lymphomas and sarcomas. We have previously shown that PMS2(-/-) mice were hypersensitive to a single i.p. injection of 50 mg/kg of N-methy l-N-nitrosourea (MNU) for thymic lymphoma induction. We postulated that MNU sensitivity was due to formation of O-6-methylguanine (O-6-mG), which, if unrepaired by O-6-alkylguanine DNA alkyltransferase (AGT), leads to apoptos is in MMR competent cells and O-6-mG:T mismatches in MMR deficient cells. T umor induction is less in MMR+/+ mice because cells with residual DNA adduc ts die, whereas mutagenized cells survive in MMR-/- mice. Overexpression of AGT (encoded by the methylguanine DNA methyltransferase-MGMT-gene) is know n to block MNU induced tumorigenesis in mice with functional MMR, To furthe r determine the sensitivity of PMS2(-/-) mice to MNU and the protective eff ect of hAGT overexpression, a low dose of MNU (25 mg/kg) was studied in PMS 2(-/-) mice and PMS2(-/-)/hMGMT(+) mice. No thymic lymphomas were found in MNU-treated PMS2(+/+) and PMS2(+/-) mice. At 1 year, 46% of the MNU-treated PMS2(-/-) mice developed thymic lymphoma, compared with an incidence of 25 % in both untreated PMS2(-/-) mice and MNU treated PMS2(-/-)/ hMGMT(+) mice , In addition, a significantly shorter latency in the onset of thymic lymph omas was seen in MNU-treated PMS2(-/-) mice. K-ras mutations were detected almost equally in the thymic lymphomas induced by MNU in both PMS2(-/-) and PMS2(-/-)/hMGMT(+) mice, but not in the spontaneous lymphomas, These data suggest that PMS-/- mice are hypersensitive to MNU, that there are differen t pathways responsible for spontaneous and MNU induced thymic lymphomas in PMS2(-/-) mice, and that overexpression of hMGMT protects the mice by block ing non-K-ras pathways.