title: CD3-epsilon overexpressed in prothymocytes acts as an oncogene.
abstract: BACKGROUND
  Upon engagement of the T cell receptor for antigen, its associated CD3 proteins recruit signal transduction molecules, which in turn regulate T lymphocyte proliferation, apoptosis, and thymocyte development. Because some signal transducing molecules recruited by CD3-epsilon, i.e., p56lck and p59fyn, are oncogenic and since we previously found that overexpression of CD3-epsilon transgenes causes a block in T lymphocyte and NK cell development, we tested the hypothesis that aberrant CD3-epsilon signaling leads both to abnormal T lymphocyte death and lymphomagenesis.
  
  
  METHODS
  Ten independently derived transgenic mouse lines were generated with four different genomic CD3-epsilon constructs. Mice either homozygous or hemizygous for each transgene were analyzed for an arrest in T lymphocyte development and for the occurrence of T cell lymphomas.
  
  
  RESULTS
  Aggressive clonal T cell lymphomas developed at very high frequencies in seven mouse lines with intermediate levels of copies of CD3-epsilon derived transgenes. However, these lymphomas were not found when high copy numbers of CD3-epsilon transgenes caused a complete block in early thymic development or when a transgene was used in which the exons coding for the CD3-epsilon protein were deleted. Analyses of a series of double mutant mice, tgCD3-epsilon x RAG-2null, indicated that lymphomagenesis was initiated in lineage-committed prothymocytes, i.e., before rearrangement of the T cell receptor genes. In addition, the transgene coding for the CD3-epsilon cytoplasmic domain and its transmembrane region induced a T cell differentiation signal in premalignant tgCD3-epsilon x RAG-2null mice.
  
  
  CONCLUSIONS
  The nonenzymatic CD3-epsilon protein acted as a potent oncogene when overexpressed early in T lymphocyte development. Lymphomagenesis was dependent on signal transduction events initiated by the cytoplasmic domain of CD3-epsilon.
authors.affiliation: Beth Israel Deaconess Medical Center, Division of Immunology, Boston, MA 02215, USA.
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: She
authors.forename: M
authors.initials: M
authors.lastname: Salio
authors.forename: D
authors.initials: D
authors.lastname: Allen
authors.forename: E
authors.initials: E
authors.lastname: Lacy
authors.forename: N
authors.initials: N
authors.lastname: Lonberg
authors.forename: C
authors.initials: C
authors.lastname: Terhorst
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000502:physiology*; D016923:Cell Death; D003593:Cytoplasm; D004268:DNA-Binding Proteins; D008198:Lymph Nodes / Q000473:pathology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D016399:Lymphoma, T-Cell / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009857:Oncogenes / Q000502:physiology*; D011506:Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology*; D013945:Thymoma; D013950:Thymus Gland / Q000166:cytology / Q000254:growth & development* / Q000473:pathology; D019061:src-Family Kinases / Q000502:physiology
chemical_list: D017252:CD3 Complex; D004268:DNA-Binding Proteins; D011506:Proteins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases