Phosphatidic acid induces the differentiation of human acute promyelocytic leukemic cells into dendritic cell-like

We investigated whether phosphatidic acid (PA) can differentiate the promyelocytic leukemia (PML)-retinoic acid receptor α (RARα)- expressing acute promyelocytic leukemiccell line, NB4, to dendritic cell (DC)-like cells. Dioctanoyl-PA alone upregulated the expression of DC markers. The expression of DC markers on NB4 cells was potentiated by the overexpression of phospholipase D and upregulation was blocked by the addition of n-butanol, an inhibitor of PA production. The expression of CD11c, CD83, and CCR7 in PA-treated NB4 cells was further increased by tumor necrosis factor (TNF)-α treatment. Increased functional capacities were also found in PA-differentiated and TNF-α-activated NB4 cells with respect to changes in T-cell proliferation, cytokine production, endocytic activity, and cytolytic capacity against undifferentiated NB4 cells. PA alone increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. The expression of DC markers was downregulated by PD98059, a specific inhibitor of ERK kinase or transient transfection of mutant-ERK. The level of PML-RARα fusion protein was decreased by PA treatment and PD98059 blocked the decrease of PML-RARα. These results suggest that PA induces differentiation of NB4 cells into DC-like cells and that the upregulation of antigen presenting cell markers is mediated by the activation of ERK and the downregulation of PML-RARα levels.