MECHANISM(S) OF LEUKEMOGENESIS IN GENETICALLY-ALTERED MOUSE MODELS

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Leukemia incidence is increasing, especially in children, and the contribution of ubiquitous exposure to environmental leukemogens is unknown. Since mutated ras oncogene is the most frequent abnormality reported in myelodysplastic syndromes and acute myeloid leukemias in humans, we chose to use the z-globin promoted v-Ha-ras Tg.AC transgenic line to investigate the role of an inducible oncogenic ras in the induction of leukemia after exposure to benzene (BZ). Here we describe the morphological and immunophenotypic analysis as well as a spleen colony assay data, to demonstrate that repeated dermal exposure of Tg.AC mice to BZ, but not the nontransgenic parent strain FVB/N, induced a myelogenous leukemia. Profound anemia and marked neutrophilia with presence of a left shift, marked increase in the number of progenitors that differentiated to granulocytes in bone marrow, and infiltration of hematopoietic tissues by myeloid cells characterized the BZ-induced disease. Transformation of a hematopoietic cell was confirmed by transplantation experiments to isogenic, irradiated FVB/N recipients. The absence of symptoms in untreated Tg.AC, as in nontransgenic parent strain, indicated a role for the v-Ha-ras transgene message in the development of BZ-induced myelogenous leukemia. We propose that BZ-induction of the transgene occurred in a bone marrow (BM) progenitor directed toward the granulocytic lineage. By in situ hybridization (ISH) analysis, reverse transcription polymerase chain reaction (RT-PCR) assay and immunohistochemistry staining, here we demonstrated that only leukemic recipient spleen and leukemic donor spleen and liver expressed the inducible ras transgene message concomitant to mitotic activity of hematopoietic blasts. Contrary to control, none of the BZ-treated Tg.AC BM cells expressed the transgene message, possibly due to BZ metabolite toxicity for progenitors. However, recipient mice injected with normal Tg.AC BM cells that express the transgene message did not develop leukemia, suggesting that cell transformation required other mutation(s). Finally, a ribonuclease protection analysis (RPA) demonstrated that the alteration of cytokines in BZ-treated BM could promote the survival of a transformed cell. We hypothesize that the combination of v-Ha-ras activation in a progenitor and the alteration of the cytokines in BM were permissive for a clone of transformed cell to acquire new mutation(s) and the myelogenous leukemia to develop from MPD. - benzene, cancer, leukemia, transgenic, loss of heterozygosity, p53, tumor suppressor gene, ras, protooncogene