Induction of retinoic acid receptor-alpha 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 (GM-CSF) 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 RAR alpha 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 RAR alpha is induced synergistically by treatment with ATRA + GM-CSF. These results suggest that GM-CSF stimulates transcriptional activity mediated via RAR alpha in ML-1 cells. The induction of RAR alpha by GM-CSF may therefore be a mechanism for stimulation by GM-CSF. The induction of RAR alpha 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 + GM-CSF. We also found that GM-CSF induced the expression of RAR alpha 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.
Shimizu
T
T
Department of Hygiene-Chemistry, Faculty of Pharmaceutical Sciences, Science University of Tokyo, Japan.
Takeda
K
K
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins; D009244:NAD+ Nucleosidase / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis* / Q000235:genetics; D020218:Response Elements / Q000187:drug effects / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D013268:Stimulation, Chemical; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; C000607071:RARA protein, human; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1