Stem Cells, Vol 13, 295-310, Copyright © 1995 by AlphaMed Press

ORIGINAL ARTICLES

Benzene and its metabolite, hydroquinone, induce granulocytic differentiation in myeloblasts by interacting with cellular signaling pathways activated by granulocyte colony-stimulating factor

BA Hazel, A O'Connor, R Niculescu and GF Kalf
Department of Biochemistry and Molecular Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

Chronic exposure of humans to benzene (BZ) causes acute myelogenous leukemia. These studies determined whether BZ, or its reactive metabolite, hydroquinone (HQ), affect differentiation of myeloblasts. BZ or HQ administered to C57BL/6J mice specifically induced terminal granulocytic differentiation of myeloblasts. The ability of the compounds to induce differentiation of the myeloblast was tested directly using the murine 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 D4 (LTD4), an essential effector of granulocytic differentiation. Differentiation was prevented by sphinganine, a kinase C inhibitor, as well as by LPO inhibitors and LTD4 receptor antagonists. BZ and HQ also induced differentiation in 32D.3 (G) myeloblasts. Both compounds interact with cellular signaling pathways activated by granulocyte colony-stimulating factor (G-CSF) and thus replace the requirement for G-CSF. IL-3 induces a growth response, whereas G-CSF provides both growth and differentiation signals. BZ does not induce growth in the absence of IL-3, but provides a differentiation signal. Both HQ and LTD4 induce differentiation and synergize with IL-3 for growth, however, neither support growth in the absence of IL-3. BZ-induced 32D cells showed a gradual progression of progenitor differentiation to granulocytes similar to that seen with G- CSF or LTD4. HQ blocks differentiation at the myelocyte stage; only a small percentage of progenitors proceed to granulocytes. BZ, like G- CSF, upregulates LTD4 production, whereas HQ obviates the requirement for LTD4 by activating the LTD4 receptor.

This article has been cited by other articles:

				D. E. Bergsagel, O. Wong, P. L. Bergsagel, R. Alexanian, K. Anderson, R. A. Kyle, and G. K. Raabe Benzene and Multiple Myeloma: Appraisal of the Scientific Evidence Blood, August 15, 1999; 94(4): 1174 - 1182. [Full Text] [PDF]

				B. Hazel, C Baum, and G. Kalf Hydroquinone, a bioreactive metabolite of benzene, inhibits apoptosis in myeloblasts Stem Cells, November 1, 1996; 14(6): 730 - 742. [Abstract]