Synergistic induction of gene expression during the differentiation into mature macrophage in human myeloblastic leukemia cells treated with TPA and KH1060

Treatment of human myeloblastic leukemia ML-1 cells with the phorbol ester TPA in combination with the vitamin D3 analogue KH1060 will induce a synergistic differentiation to mature macrophage with multinuclei. To investigate the mechanism underlying this differentiation and the synergistic effect, a cDNA microarray and Northern blot analysis were used to examine gene expression profiles of ML-1 cells treated with TPA and/or KH1060. Results show that KH1060 enhanced several TPA-induced gene expressions and that TPA enhanced several KH1060-induced gene expressions. Studies with inhibitors of signaling molecules suggested that PKC and MAPK pathways play an important role in the differentiation induced by TPA and KH1060, and that they are associated with the synergistic induction of genes. The results of this study indicate the possibility that the expression of various genes are induced synergistically by cross-talk between TPA and KH1060 signals. It is likely that the synergistic effect on gene expression leads to the synergistic induction of differentiation by both reagents.