Hematopoietic Cell Maturation Is Regulated by Maintaining a Balance against Cytokine Induced-Cell Proliferation - Clinical Application for Differentiation-inducing Therapy of Leukemia-

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Using a factor-dependent cell line MO7ER, which contains a stably transduced human erythropoietin (EPO) receptor gene in human megakaryoblastic cell line MO7e and which resulted in concomitant expression of EPO receptor, c-Mpl and c-Kit, we investigated the biological effects of these cytokines in terms of cell growth and differentiation. Thrombopoietin (TPO), EPO and Steel factor (SLF) all stimulated MO7ER cell proliferation in a dose-dependent manner. Combined stimulation of cells with SLF plus either TPO or EPO resulted in striking synergistic enhancement of MO7ER cell growth as compared with each cytokine alone, whereas combination of TPO plus EPO showed only an additive effect on cell proliferation. With regards * cell differentiation, either TPO or EPO treatment induced enhancement of platelet glycoprotein (GP) IIb/IIIa and GPIb expression. SLF induced GPIIb/IIIa and GPIb expression, but the effect was much weaker than that of EPO or TPO. However, addition of SLF to either TPO- o … More r EPO-containing cultures (which induced potent mitogenesis in MO7ER cells) resulted in suppression of these megakaryocyte specific antigens. Addition of low-dose cytosine arabinoside (Ara-C)(1 to 10 ng/ml) enhanced TPO- or EPO- induced megakaryocytic differentiation in MO7ER cells while mildly suppressing cell growth. Treatment the cells with low-dose Ara-C plus TPO plus SLF overrode the proliferative enhancing effects of SLF and induced GPIIb/IIIa and GPIb expression as efficient as TPO alone. Retardation of TPO-induced megakaryocytic maturation was also observed in normal murine bone marrow cells by combined stimulation with TPO and SLF as assessed by the numbers of acetylcholinesterase staining-positive cells and megakaryocyte nuclear polyploidy. In addition, combination of low-dose Ara-C plus G-CSF enhanced granulocytic differentiation in WEHI-3B cells, as compared with the cells treated with G-CSF alone. This phenomenon was also reproduced using the primary cultured leukemia cells which were isolated from the patients with various types of acute myelogenous leukemias,These results suggest that hematopoietic cell maturation is, at least in part, regulated by countering cytokine-induced cell proliferation. Less