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Published online before print August 2, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0905502

Received for publication September 7, 2005.
Revised June 16, 2006.
Accepted for publication June 19, 2006.

Article

Granulocyte macrophage colony-stimulating factor enhances retinoic acid-induced gene expression

Department of Hygiene-Chemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Japan

^@ To whom correspondence should be addressed. E-mail: takahisa{at}rs.noda.tus.ac.jp.

	Abstract

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 Northen 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.

Key Words: leukemia • differentiation • GM-CSF • cDNA microarray