Mechanism(s) of Leukemogenesis in Genetically-Altered Mouse Models

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Leukemia, which is particularly severe in childhood cases, is the result of genetic and environmental interaction and dysfunction of the blood forming tissues. Public health concern over benzene is warranted because it is released into the environment from both natural and industrial sources and has become ubiquitous in air, water, soil, and, subsequently, in food and beverages. Benzene is carcinogenic to both humans and laboratory rodents. At high levels of exposure (< 30 ppm) benzene is associated with depression of blood forming elements leading to anaplastic anemia, followed by myelodysplastic syndrome (MDS) and, ultimately, to leukemia. The effect of long term exposure to relatively low levels of benzene is unknown. Experimental animal models of benzene induced leukemogenesis have not been successfully developed and, thus, mechanistic studies of benzene induced leukemogenesis under defined experimental conditions are lacking. Using the genetically altered mouse line Tg.AC, which carries two copies of an inducible viral Harvey ras (v-H-ras) gene, we have been able to demonstrate the induction of both skin tumors and myeloid leukemia after dermal exposure to high levels of benzene. Further investigation has revealed that the topical application of benzene induced suppression of both erythroid (red cell) and myeloid (white cell) components is followed by development of a myeloid leukemia in the bone marrow which invade the spleen, liver, lungs, and peripheral blood. Leukemia bone marrow cells transplanted to irradiated syngeneic non-genetically altered hosts develop foci, which show a high proportion of blast-like cells that undergo differentiation to immature granulocytes, and express the inducible v-H-ras transgene. Presently, we are investigating the genetic changes associated with this transformation that occur during benzene exposure. Development of an experimental model for benzene induced leukemia in a short term bioassay may allow us to determine: (1) a mechanistic basis for leukemogenesis under these experimental conditions and the genetic factors that play a role in susceptibility and (2) strategies for intervention and prevention.