Overexpression of human O-6-alkylguanine DNA alkyltransferase (AGT) prevents MNU induced lymphomas in heterozygous p53 deficient mice

O-6-alkylguanine DNA alkyltransferase (AGT) is a key mechanism in the preve ntion against MNU induced malignant transformation by removal of O-6 methyl guanine (O(6)mG) adducts. We asked whether heterozygous p53 deficient mice (p53+/-) would be more susceptible to MNU induced lymphomas than wild type mice, and whether O(6)mG adducts were responsible for this susceptibility. To determine whether MGMT overexpression would be protective, p53+/- mice were bred to human MGMT transgenic mice (MGMT+) and treated with 50 mg/kg M NU. MNU increased the incidence of thymic lymphomas in non-transgenic p53 / - mice from 23% (n = 13) to 68% (n = 22) and decreased the mean latency from 433 to 106 days (P=0.01 compared to untreated mice). Wild type mice ha d an incidence of 30% (n = 38) and a mean latency of 135 days after MNU. Ov erexpression of MGMT in the thymus of p53 + / - mice significantly reduced the lymphoma incidence from 68 to 28% (n = 17) and increased the latency fr om 106 to 167 days (P=0.003). Similarly, the lymphoma incidence in MGMT + / wild type mice decreased from 30 to 8% (n = 12) and the latency increased t o 297 days (P=0.2). Loss of the wild type allele was found in only 2/17 lym phomas occurring in p53 + / - mice and there were no significant point muta tions in exons 5-8 of p53. Furthermore, there was no loss of p53 function i n these mice. These data demonstrate that unrepaired O(6)mG lesions act coo peratively with the reduced p53 dose and lead to lymphomagenesis in p53+/- mice, but AGT overexpression and rapid removal of O(6)mG adducts is protect ive.