M-CSF and 1,25 dihydroxy vitamin D3 synergize with 12-O-tetradecanoylphorbol-13-acetate to induce macrophage differentiation in acute promyelocytic leukemia NB4 cells.
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NB4 cells were derived from a patient with acute promyelocytic leukemia (APL) and, unlike HL-60 cells, display the characteristic translocation t(15:17) involving the RAR alpha receptor. NB4 cells differentiate into granulocytes in response to all-trans retinoic acid, but little is known about the ability of these cells to form monocytes and macrophages. We show here that NB4 cells treated individually with a variety of agents, including recombinant human macrophage colony-stimulating factor (M-CSF), 1,25 dihydroxy vitamin D3 (1,25 D3) or 12-O-tetradecanoyl-phorbol-13-acetate (TPA), resulted in only partial or incomplete differentiation along the monocyte/macrophage pathway. However, when M-CSF was combined with TPA, or 1,25 D3 with TPA, a synergistic response was observed such that differentiation to fully functioning monocytes or macrophages occurred. In contrast, 1,25 D3 with M-CSF resulted in only a modest increase in the number of non-specific esterase positive cells and no increase in the phagocytic activity (ingestion of latex beads) when compared to either agent alone. We suggest that TPA and 1,25 D3 are monocyte/macrophage-specific differentiation inducing agents in NB4 cells but that both are required to achieve optimal macrophage function. We suggest a model for the synergistic action of TPA and 1,25 D3 and propose that inducing monocytic differentiation could also be considered in designing clinical protocols for the treatment of acute leukemia.
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