A research project has been designed to better understand the role of stem and progenitor cell differentiation and cytogenetic damage in chemical leukemogenesis. Benzene and a number of chemotherapeutic agents produce acute myelogenous leukemia (AML) via a multifactorial process which is not well understood and for which no initiation-promotion paradigms have been established either in man or experimental animals. The target hematopoietic stem and progenitor cell (HPC) compartment appears to be tightly regulated with respect to differentiation, commitment and proliferation. We hypothesize that leukemia secondary to environmental chemical or drug exposure involves a multifactorial process in which the initial step is an expansion of the proliferating HPC population at risk, followed by subsequent heritable changes that occur as a consequence of replication-dependent insult or error. This initial increase in replicating HPC does not necessarily require genomic change and may be reversible. We have recently demonstrated that the benzene metabolite hydroquinone (HQ) significantly enhances the colony-forming response of murine HPC to granulocyte/macrophage colony-stimulating factor (rGM-CSF) in culture. Studies reveal that this is an intrinsic effect on HPC, resulting in recruitment of a resting population not normally responsive to activation by GM-CSF. Using bone marrow culture, equilibrium/kinetic ligand-receptor binding, cellular fractionation and immunoblotting techniques, the molecular mechanism(s) of HQ-enhanced cytokine response will be characterized in murine HPC in order to determine whether these events are more likely the result of alterations in the function of the GM-CSF receptor complex, signal transduction, or down-regulation of receptor expression. These results will be compared with analogous experiments in human bone marrow cells. The leukemia paradigm will be further evaluated and extended by studying the effects a variety of prototype leukemogenic and nonleukemogenic chemotherapeutic agents on cytokine response in murine and human bone marrow cells. Following characterization and optimization of the concentration-dependent effects of benzene metabolites on replicating HPC in liquid and long term bone marrow cultures, additional experiments will employ chromosome G-banding analysis to characterize the frequency and identity of persistent chromosomal aberrations in replicating murine and human HPC. It is hoped that these studies will lead to a rational basis for the evaluation of the leukemogenic potential of environmental and chemotherapeutic agents by providing insight into the mechanisms of altered HPC differentiation, proliferation, subsequent cytogenetic damage and their role in chemical leukemogenesis.
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