The v-rel oncogene promotes malignant T-cell leukemia/lymphoma in transgenic mice

Abstract

The oncogene product from the avian reticuloendotheliosis virus strain T, v-Rel, is a member of the Rel/ NF-κB family of transcription factors. The mechanism by which v-Rel induces oncogenic transformation remains unclear. Several attempts to transform mammalian cells with v-Rel have failed, suggesting that v-Rel transformation may be a species-specific event. However, here we demonstrate that v-Rel, but not a truncated c-Rel, expressed under the control of the lck promoter, efficiently induced malignancies in transgenic mice. Most of the animals died before 10 months of age and developed immature, multicentric aggressive T-cell leukemia/lymphomas. Most tumors contain CD4+CD8+ cells or CD4-CD8+ cells, which have an immature rather than a mature peripheral phenotype. No tumor development was observed in control litter-mates and transgenic mice expressing a truncated form of c-Rel. Tumor formation was correlated with the presence of constitutive p50/v-Rel DNA binding activity and overexpression of several κB-regulated genes in v-rel transgenic thymocytes. However, v-Rel is also transforming in transgenic thymocytes lacking p50, indicating that p50/v-Rel heterodimer formation is not essential for the transforming activity of v-Rel. The transforming activity of v-Rel in p50 null mice has been identified as v-Rel/v-ReI homodimers. Since tumors represent immature T-lymphocytes, constitutive v-Rel expression appears to be leukemogenic at earlier stages of T-cell development. These v-Rel mice should aid in the study of lymphoma development, T-cell development and NF-κB regulation.