Recent studies have suggested that cellular transformation by abl oncoproteins may be mediated by the ras signaling pathway. One of the main nuclear targets of this signal transduction cascade is the Fos and Jun family of transcription factors. To test the relevance of the c-fos proto-oncogene for v-abl-induced cancer development, we inoculated c-fos-deficient mice with the Abelson murine leukemia virus. Neonatal c-fos-deficient mice infected with the Abelson complex are able to develop the pre-B-cell lymphoma that characterizes Abelson disease. c-fos-deficient animals succumb to the disease with similar kinetics as their wild-type and heterozygous littermates. Moreover, the transformed cell that brings about the malignancy in mutant mice is the same pre-B-cell lymphoblast that is seen in control animals. These results demonstrate that c-fos is not required for in vivo transformation by v-abl.