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Development of a murine orthotopic model of leukemia: evaluation of TP53 gene therapy efficacy
G Bossi1, R Scardigli, P Musiani
1Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute--Centro Richerche Sperimentali, Rome, Italy.
Abstract:
The onco-suppressor gene TP53 has potential use in the gene therapy of many human cancers including leukemias. The latter indication derived from numerous 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-transduced leukemia cells. Thus, we developed an orthotopic leukemia model in adult, syngenic mice to evaluate the feasibility of TP53-mediated therapeutic approaches. We found that among other cells, v-src-transformed 32D myeloid progenitors induce leukemia when injected intravenously in syngenic mice. The 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 macroscopic or microscopic infiltration of the kidneys, liver, and lungs. When these 32Dv-src cells were infected with a TP53-recombinant retrovirus before intravenous injection, we found a decreased mortality and, in those animals that develop leukemia, a drastic reduction of the generalized organ infiltration, suggesting that exogenous TP53 expression might be used for ex vivo bone marrow purging from leukemia cells.
Insights
Introducing the tumor suppressor gene TP53 (p53) for leukemia gene therapy. This study shows p53 reduces leukemia cell invasion and mortality in a novel mouse model, suggesting its therapeutic potential.
Area of Science:
- Oncology
- Gene Therapy
- Cancer Research
Background:
- The tumor suppressor gene TP53 (p53) shows promise for treating various cancers, including leukemias.
- In vitro studies demonstrate p53's suppressive effects on leukemia cells, but in vivo validation is limited.
Purpose of the Study:
- To develop and utilize an orthotopic leukemia mouse model for evaluating TP53-mediated gene therapy.
- To assess the in vivo efficacy of exogenous TP53 expression in combating leukemia.
Main Methods:
- Development of an orthotopic leukemia model using intravenously injected v-src-transformed 32D myeloid progenitors in syngenic mice.
- Infection of leukemia cells with a TP53-recombinant retrovirus prior to injection.
- Evaluation of mortality rates and organ infiltration in treated and untreated leukemia models.
Main Results:
- The orthotopic model successfully recapitulated human acute myeloid leukemia characteristics, including bone marrow invasion and organ infiltration.
- Mice injected with TP53-transduced leukemia cells exhibited reduced mortality and significantly decreased organ infiltration.
- Exogenous TP53 expression demonstrated a suppressive effect on leukemia progression in vivo.
Conclusions:
- The developed orthotopic leukemia model is suitable for evaluating TP53-based gene therapy.
- Exogenous TP53 expression can mitigate leukemia progression and organ invasion in vivo.
- TP53 holds potential for ex vivo purging of leukemia cells from bone marrow for therapeutic applications.