BENZENE AND ITS METABOLITE, HYDROQUINONE, INDUCE GRANULOCYTIC DIFFERENTIATION IN MYELOBLASTS BY INTERACTING WITH CELLULAR SIGNALING PATHWAYS ACTIVATED BY GRANULOCYTE-COLONY-STIMULATING FACTOR

Chronic exposure of humans to benzene (BZ) causes acute myelogenous le ukemia. These studies determined whether BZ, or its reactive metabolit e, hydroquinone (HQ), affect differentiation of myeloblasts, BZ or HQ administered to C57BL/6J mice specifically induced terminal granulocyt ic differentiation of myeloblasts. The ability of the compounds to ind uce differentiation of the myeloblast was tested directly using the mu rine interleukin 3 (IL-3)-dependent myeloblastic cell line, 32D.3 (G) and the human HL-60 promyelocytic leukemic cell line, Treatment of HL- 60 myeloblasts with BZ activated protein kinase C and upregulated the 5-lipoxygenase (LPO) pathway for the production of leukotriene D-4 (LT D(4)), an essential effector of granulocytic differentiation. Differen tiation was prevented by sphinganine, a kinase C inhibitor, as well as by LPO inhibitors and LTD(4) receptor antagonists, BZ and HQ also ind uced differentiation in 32D.3 (G) myeloblasts, Both compounds interact with cellular signaling pathways activated by granulocyte colony stim ulating factor (G-CSF) and thus replace the requirement for G-CSF, IL- 3 induces a growth response, whereas G-CSF provides both growth and di fferentiation signals, BZ does not induce growth in the absence of IL- 3, but provides a differentiation signal, Both HQ and LTD(4) induce di fferentiation and synergize with IL-3 for growth, however, neither sup port growth in the absence of IL-3, BZ-induced 32D cells showed a grad ual progression of progenitor differentiation to granulocytes similar to that seen with G-CSF or LTD(4) HQ blocks differentiation at the mye locyte stage; only a small percentage of progenitors proceed to granul ocytes. BZ, like G-CSF, upregulates LTD(4) production, whereas HQ obvi ates the requirement for LTD(4) by activating the LTD(4) receptor.