Final Report: Comparative Studies in the Field of Mouse and Human Leukemia, June211 1, 1991-October 31, 1994

摘要

Early in the work on this grant the authors established that the growth factor-211u001edependence of radiation-induced thymic leukemia cells was dependent on the 211u001eautocrine/paracrine growth factor IL-4. Localized, thymic leukemias always grew 211u001eby virtue of an IL-4-driven autocrine/paracrine pathway. They continued and 211u001einvestigated the mechanism of progression of the thymic leukemias to the later, 211u001edisseminate disease. Linking the generation of disseminated leukemias to their 211u001egrowth factor-dependent status (10,11), they found that the development of growth 211u001efactor-independence was associated with the dissemination of the leukemia from 211u001ethe thymus to other sites, e.g. spleen, lymphnodes, liver and kidney (9,8). 211u001eIndeed, all disseminated leukemias were composed of growth factor-independent 211u001ecells. The generation of disseminated radiation-induced leukemia is associated 211u001ewith the loss of specific differentiation antigens and the mutation of the p53 211u001etumor suppressor gene. The thymic, growth factor-independent leukemia carried non-211u001emutated, wild type p53 (4). These results suggested that it might be possible to 211u001einfluence the dissemination (6,7) of leukemia cell propagation in vivo by the re-211u001eintroduction of wild type p53 into the leukemias cells. They could show that the 211u001etransduction of genes encoding specific mutant p53 proteins enhanced their 211u001edissemination potential and, in addition, the transduction of constructs encoding 211u001ewild type p53 reversed the disseminated phenotype--and the leukemic phenotype--of 211u001emurine and human acute leukemia cells. As a result of the DOE grant, and to 211u001efurther study the gene-transduction approach for the inhibition of leukemia and 211u001eother cancer cells, they developed an acute retroviral gene transfer system that 211u001ewas capable of the rapid generation of high-titer retroviral virions that were 211u001enon-mutated and non-deleted (12). This system has been supplied to dozens of 211u001elaboratories in the country and is widely used in many research laboratories.