Induction of Retinoic Acid Receptor-a by Granulocyte Macrophage Colony- stimulating Factor in Human Myeloid Leukemia Cell Lines

We reported previously that treatment with all-trans retinoic acid (ATRA) and granulocyte macrophage colony-stimulating factor (GMCSF) induces differentiation of human myeloblastic leukemia ML-1 cells to granulocytes, whereas treatment with ATRA alone induces practically no differentiation of these cells. To investigate the mechanism of the synergistic effect of these factors, we examined the effect of GM-CSF on retinoic acid receptors (RARs) and retinoid X receptors (RXRs) in ML-1 cells. We reveal that GM-CSF induces the expression of RARa mRNA and protein and stimulates the binding of nuclear proteins to direct repeat 5, a consensus sequence with high affinity for RAR-RXR heterodimers. Furthermore, expression of CD38 mRNA mediated through RARa is induced synergistically by treatment with ATRA 1 GM-CSF. These results suggest that GM-CSF stimulates transcriptional activity mediated via RARa in ML-1 cells. The induction of RARa by GM-CSF may therefore be a mechanism for stimulation by GM-CSF. The induction of RARa by GM-CSF was also detected in other myeloid leukemia cell lines (THP-1 and KG-1) that showed a synergistic effect similar to that seen in ML-1 cells in response to ATRA 1 GM-CSF. We also found that GM-CSF induced the expression of RARa in blood cells obtained from patients with acute myeloid leukemia. This activity of GM-CSF may serve as a useful adjunct to differentiation therapy for retinoic acid-nonresponsive leukemias.