A Transgenic Model to Study the Role of Oncogenes and Tumour Suppressor Genes in T-Cell Lymphoma

Transgenic mice have previously been used as an effective in vivo model to examine the role of genetic lesions in tumourigenesis. The work presented in this thesis describes a transgenic approach designed to investigate the consequences of deregulated c-myc and loss of the p53 tumour suppressor gene in the pathogenesis of T-cell lymphoma. Transgenic mice positive for both a CD2-myc transgene and homozygous p53 null mutation were generated by crossing these parental strains together. The p5-/-/CD2- myc+, transgenic mice developed highly malignant, clonal T-cell lymphomas with increased frequency and reduced latency compared to either genotype alone. Tumours were detected in young p53-/-/CD2-myc+ mice as early as 27 days of age with clinical manifestation of disease occurring at between 50 and 86 days of age. These studies revealed the potent synergy between deregulated c-myc and p53 loss in T-cell lymphomagenesis. The latency and clonality of p53-/-/CD2-myc+ tumours however, suggested that CD2-myc and p53-/- lesions alone were insufficient for the induction of a malignant phenotype. This interpretation was confirmed by infection of p5347CD2-myc+ neonatal mice with Moloney murine leukaemia virus (MoMuLV) which resulted in a further acceleration of tumour onset. The mechanism of synergy between CD2-myc and p53-/- is unclear but gross examination of malignant tumours demonstrated that the levels of apoptosis in p53-/-/CD2-myc+ lymphomas were not significantly different to parental groups. This suggests that p53-dependent, c-myc mediated apoptosis does not appear to play a major role at this stage of tumour development. Tumourigenesis was not accelerated in animals heterozygous for the p53 null mutation suggesting that loss of both wild type p53 alleles was required for efficient synergy with the CD2-myc transgene. However studies on p53-/-/CD2-myc+ mice implied that loss of the remaining allele could confer a selective advantage on c-myc expressing tumour cells. Loss of the p53 tumour suppressor gene also collaborated with MoMuLV infection in the development of murine T-cell tumours. However the relatively weak synergy between these lesions compared to that observed with p53 loss and deregulated c-myc may be suggestive of a functional overlap between MoMuLV and p53 loss