THE EFFECTS OF BENZENE AND OTHER LEUKEMOGENIC AGENTS ON HEMATOPOIETICSTEM AND PROGENITOR-CELL DIFFERENTIATION

A characteristic shared by a diverse group of myelotoxic compounds and leukaemogens is the ability to act synergistically with granulocyte-m acrophage colony stimulating factor (GM-CSF) in increasing clonogenic response. Pretreatment of murine or human bone marrow cells with the b enzene metabolite, hydroquinone, but not phenol, catechol or trans, tr ans-muconaldehyde, results in a selective enhancement of GM-CSF but no t an interleukin-3 (IL-3)-mediated clonogenic response. Clonal enhance ment is preserved and magnified in enriched populations of CD34(+) cel ls (> 95% purity), suggesting an intrinsic effect on haematopoietic pr ogenitor cell (HPC) recruitment rather than a secondary effect involvi ng accessory cytokines. Clonogenic enhancement of murine HPCs is not a ccompanied by alterations in GM-CSF receptor expression or Ligand affi nity and appears to be mediated via a p53-independent mechanism. These observations suggest that hydroquinone treatment alters recruitment a nd differentiation in a primitive subpopulation of CD34(+) cells and a re consistent with a role for altered stem cell differentiation in the development of chemically induced myelodysplasias.