IMPACT OF BENZENE METABOLITES ON DIFFERENTIATION OF BONE-MARROW PROGENITOR CELLS

Interleukin-3 (IL-3) and granulocyte/macrophage-colony-stimulating fac tor (GM-CSF) are responsible for maintaining survival and stimulating growth of early dormant hematopoietic progenitor cells (HPC). These cy tokines exhibit extensive overlap, with GM-CSF supporting growth and d ifferentiation of myeloid HPC. A characteristic shared by a diverse gr oup of leukemogens is the ability to act synergistically with GM-CSF t o increase clonogenic response. Previous studies have revealed that pr etreatment of murine HPC with hydroquinone (HQ) but not phenol, catech ol, or trans-trans-muconaldehyde results in a selective enhancement of GM-CSF but not IL-3-mediated clonogenic response. Pretreatment of mur ine bone marrow cells with these agents or their metabolites in vitro results in increased numbers of HPC dividing and forming colonies in r esponse to GM-CSF but not IL-3. The present studies explored the molec ular mechanisms associated with altered cytokine response in early HPC in murine bone marrow and extended our initial observations in murine bone marrow to human bone marrow cells. HQ pretreatment of murine HPC did not induce either an up- or a down-regulation of GM-CSF receptors or any change in receptor affinity. CD34(+) cells, which represent be tween 1 and 5% of human bone marrow, contain virtually all clonogenic stem and HPC. Pretreatment of CD34(+) cells (similar to 95% purity) wi th HQ also results in enhanced clonogenic response with GM-CSF but not IL-3. These findings suggest that an early step in chemical leukemoge nesis may involve transient alterations in the regulation of cytokine response to GM-CSF.