POTENTIATION OF LYMPHOMAGENESIS BY METHYLNITROSOUREA IN MICE TRANSGENIC FOR LMO1 IS BLOCKED BY O-6-ALKYLGUANINE DNA-ALKYLTRANSFERASE

We evaluated induction of lymphomas by the methylating carcinogen, N-m ethylnitrosourea [MNU], in transgenic mice expressing both LMO1 and th e DNA repair gene, MGMT, in the thymus, The goal was to determine whet her environmental mutagens shorten the latency or increase the inciden ce of LMO1+lymphomas and whether mice transgenic for both LMO1 and MGM T, and thereby able to repair O-6-methylguanine DNA adducts induced by MNU, would be protected, Mice heterozygous for LMO1 or MGMT were cros sed and offspring treated with MNU at 6 weeks of age, MNU induced lymp homa incidence was highest in the LMO1 mice, 91% and lowest in the hMG MT+mice, 15%, MNU induced K-ras mutations in codon 12 in non-MGMT tran sgenics resulted in a shorter latency of tumors and accounting for hal f of the early lymphomas in LMO1 mice, The effect of MNU was abrogated in the LMO1/hMGMT transgenic mice, indicating the ability of MGMT exp ression to block the carcinogenic effect of MNU even in cancer prone m ice, Thus, methylating agents potentiate lymphomagenesis of LMO1, in p art through activation of K-ras and the MAPK pathway, a process which appear to synergize with LMO1 mediated transcription activation, O-6-a lkylguanine DNA-alkyltransferase mediated DNA repair effectively block s chemical carcinogenesis in mice carrying the LMO1 oncogene.