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‐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.

Genetic approaches in mice to understand Rel/NF-κB and IκB function: transgenics and knockouts

“…Transgenic mice over-expressing the v-Rel oncoprotein (Gilmore, 1999) in thymocytes develop T-cell leukemias (Carrasco et al, 1996). The major nuclear v-Rel-containing DNA-binding complexes expressed in these tumors are v-Rel homodimers and v-Rel/p50 heterodimers.…”

“…The major nuclear v-Rel-containing DNA-binding complexes expressed in these tumors are v-Rel homodimers and v-Rel/p50 heterodimers. v-Rel-induced tumors develop faster in mice homozygous for the null allele of nfkb1, suggesting p50 retards v-Rel-mediated leukemogenesis (Carrasco et al, 1996). However, over-expression of IkBa in v-Rel transgenic mice , which selectively reduces the nuclear expression of vRel/p50 heterodimers but not v-Rel homodimers in thymocytes, retards leukemia onset and changes the characteristics of the disease.…”

Differences in κB DNA-binding properties of v-Rel and c-Rel are the result of oncogenic mutations in three distinct functional regions of the Rel protein

“…Relation between DNA-binding function and the gene induction/repression potential of the three mutation clusters present in v-Rel Several Rel/NF-kB target genes are either up or downregulated as a consequence of v-Rel's expression Carrasco et al, 1996;Hrdlickova et al, 1994bHrdlickova et al, , 1995bKralova et al, 1994;Zhang et al, 1995;Zhang and Humphries, 1996). The expression of several of these genes (MHC class I and II, IL-2R) were shown to be activated to a higher extent by v-Rel than c-Rel (Hrdlickova et al, 1994b, Nehyba et al, 1994.…”

“…All these truncated variants of c-Rel, however, are far less oncogenic than v-Rel which contains the Cterminal deletion of 118 amino acids as well as 19 additional mutations (Wilhelmsen et al, 1984) (Figure 1b, for de®nition of the term`mutations in v-Rel' see Materials and methods). Also, v-Rel, but not a truncated c-Rel, expressed under the control of the lck promoter, e ciently induced malignancies in transgenic mice (Carrasco et al, 1996). These facts underscore the importance of these additional changes in the amino acid sequence of v-Rel for the oncogenicity of this protein.…”

cRel-TD kinase: a serine/threonine kinase binding in vivo and in vitro c-Rel and phosphorylating its transactivation domain

“…The retroviral homologue, v-rel, induces aggressive lymphoma or leukemia in chickens and transgenic mice while immortalizing and transforming spleen and bone marrow cells in vitro (Lewis et al, 1981;Boehmelt et al, 1995;Carrasco et al, 1996). The protein family also includes the vertebrate RelA, RelB, p105/NF-kB1, p100/NF-kB2 (Verma et al, 1995;Baldwin, 1996) and Drosophila Dorsal and Dif (Kopp and Ghosh, 1995).…”