SJL mice spontaneously develop B-cell lymphomas that can be propagated by transplantation into syngeneic mice. These tumors usually have an indolent phenotype and require at least several weeks to produce morbidity following transplantation. However an aggressive lymphoma (RCS5) has been found that produces morbidity within days of transplantation. RCS5 cells fail to express the H-2Ds class I major histocompatibility complex antigen, whereas indolent tumors express H-2Ds. To identify genetic factors that may contribute to the tumorigenicity of B-cell lymphomas in SJL mice, tumor genomes were analyzed for mutations in cellular oncogenes. No rearrangements were detected by Southern hybridization analysis in tumors at the abl, myc, mbcl-2, Ha-ras, Ki-ras and raf loci. Indolent tumors were not rearranged at the myb oncogene, however alterations were detected in both myb alleles in RCS5. Northern hybridization analysis on RNA from in vivo-derived tumor preparations failed to detect any myb transcripts in RCS5. The loss of normal myb expression could directly contribute to the aggressive phenotype of RCS5. Alternatively, expression of the RCS5 myb allele may have contributed to early stages of tumor development. The possibilities that the observed myb mutations affect tumor aggressiveness and H-2Ds expression are discussed.