Overexpression of human O6-alkylguanine DNA alkyltransferase (AGT) prevents MNU induced lymphomas in heterozygous p53 deficient mice.
O6-alkylguanine DNA alkyltransferase (AGT) is a key mechanism in the prevention against MNU induced malignant transformation by removal of O6 methyl guanine (O6mG) adducts. We asked whether heterozygous p53 deficient mice (p53+/-) would be more susceptible to MNU induced lymphomas than wild type mice, and whether O6mG 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 MNU. 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 had an incidence of 30% (n=38) and a mean latency of 135 days after MNU. Overexpression of MGMT in the thymus of p53+/- mice significantly reduced the lymphoma incidence from 68 to 28% (n=17) and increased the latency from 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 to 297 days (P=0.2). Loss of the wild type allele was found in only 2/17 lymphomas occurring in p53+/- mice and there were no significant point mutations in exons 5-8 of p53. Furthermore, there was no loss of p53 function in these mice. These data demonstrate that unrepaired O6mG lesions act cooperatively with the reduced p53 dose and lead to lymphomagenesis in p53+/- mice, but AGT overexpression and rapid removal of O6mG adducts is protective.
Reese
J S
JS
Division of Hematology/Oncology, University Hospitals of Cleveland, Cleveland, Ohio, OH 44106, USA.
Allay
E
E
Gerson
S L
SL
D000477:Alkylating Agents; D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens; D018736:DNA Adducts; D005091:Exons; D005434:Flow Cytometry; D016158:Genes, p53; D011905:Genes, ras / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008223:Lymphoma / Q000139:chemically induced* / Q000235:genetics*; D008770:Methylnitrosourea; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism; D013953:Thymus Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors
D000477:Alkylating Agents; D002273:Carcinogens; D018736:DNA Adducts; D008770:Methylnitrosourea; D019853:O(6)-Methylguanine-DNA Methyltransferase