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 erythroleukemia has been suggested but not clearly defined. We developed a Friend virus-sensitive, p53-deficient mouse model to directly address the role of p53 in Friend erythroleukemia. When infected with the polycythemia-inducing strain of Friend virus (FVP), p53 null mice exhibited accelerated progression to erythroleukemia and accelerated death following diagnosis when compared to wild type mice. Confirmation that p53 mutations were required for disease progression was provided by sequence analysis of p53 transcripts in leukemic wild type and heterozygous mice. All transcripts evaluated had point mutations, deletions or insertions in the p53 gene. The ability to grow tumor colonies in vitro and derive cell lines was enhanced in FVP-infected p53 null animals. Although PU.1 oncogene overexpression is a common mutation observed 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 animals. Our data conclusively demonstrate that loss of p53 function is a requirement for progression of Friend erythroleukemia in vivo. Further, the data demonstrate that erythroleukemias arising in Friend virus-infected p53 null mice are biologically and genetically distinct from those that occur in wild type animals, suggesting that the temporal order of PU.1 and p53 mutations is an important parameter in the pathogenesis of leukemic development.
Prasher
J M
JM
Department of Pathology, University of Utah School of Medicine and the Huntsman Cancer Institute, Salt Lake City, Utah, UT 84132, USA.
Elenitoba-Johnson
K S
KS
Kelley
L L
LL
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005622:Friend murine leukemia virus / Q000472:pathogenicity; D016147:Genes, Tumor Suppressor; D050835:Interferon Regulatory Factors; D004915:Leukemia, Erythroblastic, Acute / Q000209:etiology / Q000235:genetics* / Q000821:virology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D015996:Survival Rate; D015534:Trans-Activators / Q000235:genetics; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000099218:Interferon Regulatory Factor-4
D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D000099218:Interferon Regulatory Factor-4