PROGRESSION OF SPONTANEOUS LYMPHOMAS IN SJL MICE - MONITORING IN-VIVOCLONAL EVOLUTION WITH MOLECULAR MARKERS IN SEQUENTIAL SPLENIC SAMPLES

SJL mice are an inbred strain with a high incidence of spontaneous lym phomas of the B-cell type. We used molecular markers of clonality to s tudy the process of tumor progression of SJL lymphomas in vivo. This w as accomplished at time intervals ranging from 2 to 116 days by initia l partial splenectomy (biopsy) followed by spleen sampling at the time of killing (autopsy). Immunoglobulin heavy chain (IgH) gene rearrange ment and murine leukemia virus (MuLV) proviral integration patterns we re used to study the clonal identities of the sequential tumor pairs i n 11 informative mice by Southern blot hybridization. Of these 11 mice , 5 showed the same number of IgH gene rearrangement bands in the matc hed biopsy-autopsy samples, indicating the persistence of the original lesions. In 2 of 11 mice, a decrease in the number of IgH gene rearra ngement bands was seen, consistent with a process of clonal selection in the original oligoclonal population. Another 2 of 11 mice showed an increase in the IgH gene rearrangement bands, indicating the emergenc e of either a new unrelated clone or, less likely,a subclone with seco ndary IgH gene rearrangement. The remaining two mice showed difference s between the patterns in biopsy and autopsy samples, as assessed by I gH gene rearrangement and the proviral integration analysis. This find ing suggests that the biopsied tumor had regressed and new clones had emerged. Tumor development was also associated with an increase in the number of clonal MuLV insertions in all mice except one, in which no non-germline integration band was detected. Of 11 mice, 5 showed an in crease in the extent of tumor involvement by microscopic examination o f the biopsy and autopsy samples; 3 showed a decrease, whereas 2 showe d no change. A change in tumor morphology toward a more dedifferentiat ed appearance was found in only 1 of 11 mice. Overall, the results did not show a single paradigm that tumor progression followed, rather th ey indicated a complex and dynamic process of clonal evolution, which is likely to be a major feature of lymphoma progression in vivo.