The v-rel oncogene promotes malignant T-cell leukemia/lymphoma in transgenic mice.
The oncogene product from the avian reticuloendotheliosis virus strain T, v-Rel, is a member of the Rel/ NF-kappa B 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 littermates 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 kappa B-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-Rel 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-kappa B regulation.
Carrasco
D
D
Department of Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
Rizzo
C A
CA
Dorfman
K
K
Bravo
R
R
D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002645:Chickens; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D020672:I-kappa B Proteins; D007376:Interleukin-2 / Q000502:physiology; D015458:Leukemia, T-Cell / Q000235:genetics*; D016399:Lymphoma, T-Cell / Q000235:genetics*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D052002:NF-kappa B p50 Subunit; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins / Q000378:metabolism; D009838:Oligodeoxyribonucleotides; D020572:Oncogene Proteins v-rel; D009857:Oncogenes; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000502:physiology; D013154:Spleen / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D007376:Interleukin-2; D008565:Membrane Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C512772:NUP107 protein, human; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D020572:Oncogene Proteins v-rel; D015682:Retroviridae Proteins, Oncogenic