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Enhanced Mitogenic Responsiveness to Granulocyte-Macrophage Colony-stimulating Factor in HL-60 Promyelocytic Leukemia Cells upon Induction of Differentiation¹

Department of Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York 10467

Treatment of HL-60 leukemia cells with the inducers of differentiation dimethyl sulfoxide (DMSO) and 6-thioguanine (TG) reduces the proliferative capacity of the cells. DMSO acted in a serum-independent manner and reversibly inhibited competence to enter S phase after 24 h of treatment. Purified human granulocyte-macrophage colony-stimulating factor (GM-CSF) but not human CSF-1, restored S phase competence and growth of DMSO-treated cells over a 7-day period. GM-CSF had no effect on the saturation density of control cells, even under conditions of reduced growth. Furthermore, GM-CSF antagonized the growth inhibitory actions of TG associated with cytodifferentiation but not those associated solely with TG cytotoxicity. The number of high affinity, cell surface GM-CSF receptors doubled after treatment of HL-60 cells with DMSO for 24 h and reached a maximum 4- to 5-fold increase within 72 h of exposure. The K_d of GM-CSF binding, 240 pM, was comparable to the concentration required to elicit a mitogenic response in DMSO-treated cells. An HL-60 variant that had been selected for resistance to TG-induced growth inhibition and differentiation (R. E. Gallagher et al., Cancer Res., 44: 2642–2653, 1984) was found to have less than 20% of the cell surface GM-CSF receptors when compared to either wild type cells, or a variant line selected for resistance to TG cytotoxicity. These studies demonstrate that HL-60 cells undergoing differentiation simultaneously lose autonomous growth properties and acquire cell surface growth factor receptors and mitogenic responsiveness.

¹ This work was supported in part by the Mathers Foundation and Grant CH-298 from the American Cancer Society.

² To whom requests for reprints should be addressed, at Department of Oncology, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467.

Received 8/19/87. Revised 12/ 5/87. Accepted 2/17/88.

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