Chemical induction of thymomas in AKR mice: Interaction of chemical carcinogens and endogenous murine leukemia viruses. Comparison of N‐methyl‐N‐nitrosourea and methyl methanesulphonate

Abstract The time course of development of thymic lymphoma, which occurs spontaneously in mice of the AKR strain, is accelerated by the methylating agents N ‐methyl‐ N ‐nitrosourea (MNU) and methyl methanesulphonate (MMS). Since MNU is a potent mutagen inducing G → A transition mutations and MMS a relatively weak mutagen, it was of interest to examine the genetic alterations associated with each class of the chemically induced tumors and to compare these alterations with those found in the spontaneous tumors. The same spectrum of genetic alterations was found for MMS‐induced and spontaneous thymomas. Both showed rearrangements of c‐ myc and Pim ‐1 genes that appeared to result from integration of recombinant mink cytopathic focus‐forming (MCF) proviruses but failed to reveal evidence for activation of ras oncogenes, either by DNA transfection experiments or by hybridization of DNA to specific oligonucleotide probes. Some alterations in c‐ myc and Pim ‐1 genes were also found in MNU‐induced tumors, but, mainly, these involved integration of ecotropic‐like rather than recombinant MCF viruses. Furthermore, MNU‐induced tumors frequently (in 24% of thymomas) contained G → A transition mutations, activating the Ki‐ ras oncogene at codon 12 position 2. Another feature that distinguishes the MNU‐induced tumors from those occurring in untreated and MMS‐treated mice was the consistently high level of c‐ myc mRNA that occurred in the absence of c‐ myc gene rearrangement. Taken together, the data indicate that the mechanisms of development of tumors following treatment with MNU and MMS are distinct, and that the effect of MMS is probably to speed up the process of viral leukemogenesis.