Friend virus induced murine erythroleukaemia: the p53 locus

The development of Friend virus induced murine erythroleukaemia is associated with specific genetic events. One of these events is loss of wild type p53 expression, which can occur by internal deletion or proviral insertion in the p53 gene and by single point mutations in the coding sequence. In all cases, the corresponding wild type allele is absent. The high frequency of observed p53 mutations strongly suggests that inactivation of p53 may be an obligatory step in the development of Friend disease. Further evidence that abrogation of normal p53 expression contributes to the development of malignant clones was provided by in vitro reconstitution experiments in Friend cell lines: whereas exogenous mutant p53 was stably expressed in p53 negative FCLs, long term wild type p53 expression was not detected. Friend erythroleukaemia arises as a late consequence of infection of susceptible mice with Friend virus. In addition to p53 gene mutations, proviral insertions occur frequently adjacent to one of two cellular genes, Spi-1/PU.1 or Fli-1. Aberrant expression of these genes may therefore be involved in virus induced erythroleukaemia. Interaction of SFFV env gp55 with the EPO-R also appears to be important in providing a mitogenic signal to infected cells. The order in which these events occur and whether the order is relevant to the progression of the disease are not known. Investigation of the stepwise appearance of these events could provide information on the possible interactions of the gene products involved. Abrogation of normal p53 expression is not restricted to Friend erythroleukaemia: the observation of p53 mutations and allele loss in human breast, lung, colon and hepatocellular carcinomas and in leukaemia suggests that mutation of p53 may be the most common genetic abnormality detected in human cancer (reviewed in this issue). Studies of p53 expression in FCLs provided an early indication that p53 was a tumour suppressor gene. Further studies of the mechanisms by which wild type and mutant p53 affect the growth of p53 negative FCLs may reveal important biochemical properties of p53 in relation to cell cycle control and differentiation of erythroid cells.