Multistage carcinogenesis in murine thymocytes: involvement of oncogenes, chromosomal imbalances and T cell growth...

An animal model of carcinogenesis has been exploited to analyze the various events involved in carcinogen-induced T cell lymphomagenesis. Two carcinogenic agents, the alkylating agent N-methylnitrosourea (NMU) and ionizing gamma-radiation, induce tumors in C57BL/6J mice that are phenotypically and histologically identical. Are the genetic events similar or different in the T cell tumors produced by these two carcinogenic agents? NMU treatment produced a different spectrum of activated oncogenes from gamma-irradiation. The K-ras oncogene was preferentially activated in all of the NMU-induced tumors, most frequently by a GGT to GAT transition in codon 12. Ionizing gamma-radiation produced two different transforming activities. Approximately half of the radiation-induced tumors contained activated N-ras genes and half contained a novel non-ras transforming activity. Analysis of NMU- and gamma-irradiated treated animals for chromosomal abnormalities showed anomalies early in the disease. Although both agents produce tumors containing trisomy of chromosome 15, the timing of this event appears to be different occurring early in NMU-induced tumors and later in gamma-radiation induced tumors. In addition, a unique marker chromosome consisting of a translocation between chromosomes one and five appears to be involved in the early stages of radiation-induced disease and may be associated with the novel transforming activity detected in these same tumors. Expression of receptors for the T cell growth factor (IL-2R) is similar in both NMU- and gamma-irradiation induced tumors. Changes in the expression of IL-2R on different T cell populations with disease progression may account for thymus dependent and thymus independent phases of malignant T cell growth.