Lineage restriction of the RARα gene expression in myeloid differentiation

To better understand the role of retinoids in myelopoiesis, expression of the retinoid receptor genes (retinoic acid receptors [RARs] and retinoid X receptors [RXRs]) were examined during differentiation of factor-dependent cell-Paterson (FRCP)-mixA4 murine progenitor cells. The major receptor expressed in undifferentiated A4 cells was RAR alpha (primarily the RAR alpha1 isoform). Following induction of myelomonocytic differentiation with granulocyte and granulocyte-macrophage colony-stimulating factors, a dramatic increase in RARa expression (particularly the RAR alpha2 isoform) was seen. In contrast, expression of both RAR alpha isoforms was rapidly extinguished upon induction of erythroid differentiation with erythropoeitin (EPO). A modest induction of RXR alpha expression was seen, particularly during differentiation in the myelomonocytic lineage. Low expression levels of RAR gamma2 and RXR beta remained unchanged, irrespective of differentiation pathway. Consistent with the gene expression patterns, RAR alpha agonists and antagonists stimulated myelomonocytic and erythroid differentiation of FDCP-mixA4 cells, respectively. Taken together, these results suggest that erythropoiesis and granulopoiesis require diminished and enhanced RAR alpha activities, respectively, which at physiological all-trans-retinoic acid (RA) concentrations may be accomplished by reciprocal effects of EPO and myelomonocytic growth factors on its expression. This hypothesis is corroborated by data showing that RA, which positively regulates RAR alpha2 expression, can exert: inhibitory effects on erythroid differentiation. (Blood. 2001;98:2563-2567) (C) 2001 by The American Society of Hematology.