SYNERGY BETWEEN A HUMAN C-MYC TRANSGENE AND P53 NULL GENOTYPE IN MURINE THYMIC LYMPHOMAS - CONTRASTING EFFECTS OF HOMOZYGOUS AND HETEROZYGOUS P53 LOSS

Activation of the c-myc oncogene and functional loss of the p53 tumour suppressor gene are among the most frequently recorded genetic lesion s in neoplasia but their combined effect has not previously been inves tigated. By breeding together mice transgenic for human c-myc (CD2-myc ) and mice carrying an inactive p53 allele (p53(-/-)) we found that th ese genetic lesions act synergistically in vivo, Offspring carrying th e CD2-myc transgene and the homozygous p53 null mutation (p53(-/-)/CD2 -myc) were viable but developed thymic lymphomas with dramatically inc reased frequency and reduced latency compared to both parental groups. The tumour phenotype was similar to that previously recorded for CD2- myc mice (predominantly CD3+, CD4+8+) but tumour clonal complexity and metastasis was significantly greater in the p53(-/-)/CD2-myc mice, In contrast, no significant increase in tumour incidence was seen in p53 (+/-)/CD2-myc vs p53(+/+)/CD2-myc mice over a 6 month observation peri od, However, the loss of wild type p53 in a proportion of tumour cells in p53(+/-)/CD2-myc lymphomas suggests that wild type allele loss can occur as a late progression step rather than an initiating step in th ese tumours, We suggest that p53 loss of function may collaborate with the CD2-myc transgene at more than one stage in thymic lymphoma devel opment.