Benzene (BZ), a Class I carcinogen, causes acute myelogenous leukemia (AML) upon chronic exposure, possibly via its bone marrow (BM) metabolite, hydroquinone (HQ). The ability to alter cytokine-dependent growth/differentiation in hematopoietic stem/progenitor cells is a property of agents with leukemogenic potential. BZ and HQ induce granulopoiesis in mice and act on the HL-60 human promyelocytic leukemia cell line. Here, it is reported that noncytotoxic concentrations of BZ or HQ can also induce granulocytic differentiation in the normal murine diploid interleukin(IL)-3-dependent myeloblastic cell line, 32D cl 3(G). BZ and HQ replace the granulocyte colony-stimulating factor (G-CSF) requirement of 32D cells for differentiation, but cannot obviate the IL-3 requirement for growth and survival. In the presence of IL-3, HQ results in a significant increase in cell number. Leukotriene D$\sb4$ (LTD$\sb4$), an intracellular effector of G-CSF-signaling, replaces BZ, HQ, or G-CSF, for differentiation of 32D cells, but cannot replace IL-3 for growth and survival. BZ and G-CSF function to upregulate LTD$\sb4$ production, whereas HQ appears to activate the LTD$\sb4$ receptor directly, bypassing the need for LTD$\sb4.$ Unlike BZ, G-CSF, or LTD$\sb4$, which induce terminal granulocytic differentiation, HQ undergoes a myeloperoxidase (MPO)-dependent oxidation to bioreactive p-benzoquinone (pBQ), which induces an incomplete program of differentiation, resulting in a predominance of myelocytes. HQ, in the presence of LTD$\sb4$, shifts LTD$\sb4$'s stage-specific pattern of terminal differentiation to its own incomplete profile. HQ's ability to increase cell number in the presence of IL-3 appears to be due to an inhibition of apoptosis, as HQ is capable of inhibiting both staurosporine (SP)- and cytokine withdrawal-induced apoptosis in myeloid cells. HQ inactivates several cysteine proteases known to be involved in apoptosis in a variety of cell types. The inability of HQ to induce a complete program of terminal granulocytic differentiation in myeloblasts and its ability to compete with induction by LTD$\sb4$, as well as its ability to inhibit apoptosis, resulting in an increase in cell number, may bear significantly on the leukemogenic potential of BZ.
