Development of a murine orthotopic model of leukemia: Evaluation of TP53 gene therapy efficacy

The once-suppressor gene TP53 has potential use in the gene therapy of many human cancers including leukemias. The latter indication derived from nume rous experimental reports of p53-mediated suppressing effects on human and murine leukemia cells in vitro. However, few in vivo experiments have been performed, and those that have used a subcutaneous injection of p53-transdu ced leukemia cells. Thus, we developed an orthotopic leukemia model in adul t, syngenic mice to evaluate the feasibility of TP53-mediated therapeutic a pproaches. We found that among other cells, v-src-transformed 32D myeloid p rogenitors induce leukemia when injected intravenously in syngenic mice. Th e resulting malignancy resembles the clinical manifestations of human acute myeloid leukemia because it is characterized by a massive invasion of bone marrow compartments, splenomegaly, generalized lymphadenopathy, and a macr oscopic or microscopic infiltration of the kidneys, liver, and lungs. When these 32Dv-src cells were infected with a TP53-recombinant retrovirus befor e intravenous injection, we found a decreased mortality and, in those anima ls that develop leukemia, a drastic reduction of the generalized organ infi ltration, suggesting that exogenous TP53 expression might be used for ex vi vo bone marrow purging from leukemia cells.