Induction of granulocytic differentiation in myeloblasts by hydroquinone, a metabolite of benzene, involves the leukotriene D-4 receptor

Chronic exposure of humans to benzene (BZ), a Class I carcinogen, causes acute myelogenous leukemia, possibly via its bone marrow metabolite, hydroquinone (HQ). The ability to alter cytokine-dependent growth and differentiation in hematopoietic stem or progenitor cells appears to be a property of agents with leukemogenic potential. We have previously reported that BZ and HQ specifically stimulate granulopoiesis in mice and cause granulocytic differentiation in normal murine interleukin (IL)-3-dependent, granulocyte colony-stimulating factor (G-CSF)-inducible 32D myeloblasts. BZ induces granulocytic differentiation by upregulating the production of leukotriene D-4 (LTD(4)), an essential intracellular mediator of G-CSF signaling. We report here that HQ (0.5-4.0 mu M), as well as LTD(4) (1 nM-10 mu M), causes a concentration-dependent induction of granulocytic differentiation in 32D myeloblasts. Unlike LTD(4), which induces terminal granulocytic differentiation, HQ undergoes a myeloperoxidase-dependent oxidation to bioreactive p-benzoquinone (BQ), which induces differentiation predominately to the myelocyte stage. Studies with the highly specific LTD(4) receptor antagonist, MK-571, suggest that BQ induces granulocytic differentiation in myeloblasts by activating the LTD(4) receptor, thus obviating the requirement for LTD(4). This was confirmed by the demonstration that HQ, in the presence of LTD(4), shifts the stage-specific pattern of terminal differentiation induced by LTD(4) to the incomplete (myelocyte) profile induced by HQ. The inability of HQ to induce a complete program of terminal granulocytic differentiation in myeloblasts, as well as its ability to compete with induction by LTD(4), may have a bearing on the leukemogenic potential of BZ.