Induction of thymomas by N-methyl-N-nitrosourea in AKR mice: interaction between the chemical carcinogen and endogenous murine leukaemia viruses

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Abstract
AKR mice develop thymomas spontaneously when >6 months old but when young AKR mice are treated with N -methyl- N -nitrosourea (MNU) they develop thymomas at 3–6 months of age. In this study the potential role of oncogene activation in the development of both the spontaneous and MNU-induced thymomas in AKR mice has been examined by DNA transfection into NTH3T3 mouse fibroblasts and by Southern analysis of tumour DNA. The results show that a high proportion of MNU-induced thymomas contain activated cellular rasK while no activated cellular ras genes were detected in spontaneous thymomas. Southern analysis of tumour DNA revealed that 2/30 spontaneous tumours and 2/52 MNU-induced tumours contained alterations in the c- myc gene while 5/29 spontaneous tumours and 6/56 MNU-induced tumours contained alterations in the Pim -1 gene. A more detailed analysis of the Pim -1 gene demonstrated that the alterations observed in most MNU-induced and spontaneous tumours resulted from proviral integration at the 3' end of this gene. Our analyses also demonstrated that the majority of MNU induced tumours, including those containing rearrangements in the Pim -1 gene, lacked the somatically acquired recombinant MCF proviruses that are present in most spontaneous AKR lymphomas. These results provide evidence that (i) the mechanisms of development of MNU-induced and spontaneous tumours in AKR mice are distinct and (ii) the development of thymomas that contain proviral integrations at the Pim -1 locus in the MNU-treated AKR mice involve cooperation between the chemical carcinogen and endogenous murine leukaemia viruses.

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