Clonal evolution of N-methylnitrosourea-induced C57BL/6J thymic lymphomas by analysis of multiple genetic alterations.

C57BL/6J mice were treated with N-methylnitrosourea (NMU) and the evolution of leukemic T-cells clones into frank thymic lymphomas was followed in 42 animals using serology of T-cell markers, rearrangements of the T-cell receptor genes gamma, beta1 and beta2 and detection of carcinogen-induced Ki-ras mutations and trisomy of chromosome 15. During the latent period, multiple populations of T-cell clones were present in the thymus, many contained trisomy 15, but few had detectable Ki-ras mutations. Since most frank lymphomas consisted of a single T-cell clone with both a mutation of Ki-ras and trisomy 15, the results imply that these two events are critical for the evolution of T-cell clones from the preleukemic phase to a more malignant disease stage. Progression to frank lymphomas is coincident with changes in the expression pattern of the T-cell growth factor interleukin-2 receptor, which may play a role in the selection, expansion and thymus-independent growth of a T-cell clone.