Granulocyte macrophage colony-stimulating factor enhances retinoic acid-induced gene expression.
We reported previously that treatment of human myeloblastic leukemia ML-1 cells with all-trans retinoic acid (ATRA) in combination with GM-CSF enhances the granulocytic differentiation, which is induced only slightly by ATRA alone. To investigate the mechanism underlying this differentiation and the synergistic effect of ATRA and GM-CSF, we used cDNA microarray to examine gene expression profiles of ML-1 cells treated with ATRA and/or GM-CSF. We identified 22 up-regulated genes in ML-1 cells treated with both reagents and examined the expression of these genes in cells treated with ATRA and/or GM-CSF by Northern blot analysis. Comparison of cells treated with both reagents and cells treated with ATRA or GM-CSF alone revealed that expression of nine of the 19 genes was induced synergistically by combined treatment with ATRA and GM-CSF. Expression of most of these genes was increased only slightly by ATRA alone, and this induction was enhanced by the addition of GM-CSF. These results indicate that GM-CSF enhances ATRA-induced gene expression. Moreover, studies with inhibitors of signaling molecules suggested that activation of JAK2 is associated with the synergistic induction of several genes by ATRA and GM-CSF. JAK2 inhibitor suppressed induction of NBT-reducing activity in ML-1 cells treated with both reagents. It is likely that the enhancer effect of GM-CSF on ATRA-induced gene expression leads to the differentiation induced synergistically by ATRA combined with GM-CSF. Further studies of the mechanism underlying this effect may identify better approaches for the treatment of RA-insensitive leukemia.
Shimizu
Takahisa
T
Department of Hygiene-Chemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan. takahisa@rs.noda.tus.ac.jp
Esaki
Lisa
L
Mizuno
Hiroko
H
Takeda
Ken
K
D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D014212:Tretinoin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor