Proviral activation of the tumor suppressor E2a contributes to T cell lymphomagenesis in EmuMyc transgenic mice.
The basic helix-loop-helix factor E2A plays an important role in the development of B and T lymphocytes. In addition, E2a has been implicated as a gene with tumor suppressor activity, since mice deficient for E2a succumb to T cell lymphomas. We have performed retroviral tagging in EmuMyc transgenic mice to identify genes that contribute to lymphomagenesis. The EmuMyc transgenic mouse is a well-established model of a common translocation in human B cell lymphomas. Analyses of the proviral insertion sites in the MuLV-induced lymphomas revealed that a number of T cell lymphomas carried proviral insertions in the promoter region of E2a. These proviral insertions yield hybrid viral-E2a mRNAs resulting in a marked rise in E2A protein levels. The proviral insertions in E2a were predominantly of clonal origin indicating that E2a insertions are early events in these T cell lymphomas. The primary oncogenic effect of E2A is likely to be associated with enhancement of transcription of the c-Myc transgene via binding to the regulatory immunoglobulin enhancers. The results herein thus provide the first evidence that in a specific setting E2A overexpression can contribute to T-lymphomagenesis. This implies that E2a contains oncogenic features in addition to the previously described tumor suppressive properties.
Mikkers
Harald
H
Division of Molecular Genetics and Centre of Biomedical Genetics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Allen
John
J
Berns
Anton
A
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D016259:Genes, myc / Q000502:physiology*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D009052:Leukemia Virus, Murine / Q000502:physiology*; D016399:Lymphoma, T-Cell / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D011533:Proviruses / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014775:Virus Activation
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D014157:Transcription Factors; C407909:TCF3 protein, human