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.
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.
Bhatia
M
M
Department of Nutritional Sciences, University of Guelph, Ontario, Canada.
Kirkland
J B
JB
Meckling-Gill
K A
KA
D002117:Calcitriol / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004950:Esterases / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology / Q000473:pathology*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010587:Phagocytosis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
D016173:Macrophage Colony-Stimulating Factor; D004950:Esterases; D002117:Calcitriol; D013755:Tetradecanoylphorbol Acetate