Loss of p53 tumor suppressor function is required for in vivo progression of Friend erythroleukemia

A role for p53 in the in vivo progression of Friend virus-induced erythrole ukemia has been suggested but not clearly defined, We developed a Friend vi rus-sensitive, p53-deficient mouse model to directly address the role of p5 3 in Friend erythroleukemia. When infected with the polycythemia-inducing s train of Friend virus (FVP), p53 null mice exhibited accelerated progressio n to erythroleukemia and accelerated death following diagnosis when compare d to wild type mice. Confirmation that p53 mutations were required for dise ase progression was provided by sequence analysis of p53 transcripts in leu kemic wild type and heterozygous mice. All transcripts evaluated had point mutations, deletions or insertions in the p53 gene. The ability to grow tum or colonies in vitro and derive cell lines was enhanced in FVP-infected p53 null animals, Although PU.1 oncogene overexpression is a common mutation o bserved in cell lines derived from Friend virus-infected p53 wild type mice , it was not a universal finding in cell lines derived from p53 null animal s. Our data conclusively demonstrate that loss of p53 function is a require ment for progression of Friend erythroleukemia in vivo. Further, the data d emonstrate that erythroleukemias arising in Friend virus-infected p53 null mice are biologically and genetically distinct from those that occur in wil d type animals, suggesting that the temporal order of PU.1 and p53 mutation s is an important parameter in the pathogenesis of leukemic development. On cogene (2001) 20, 3946-2955.