Brief report Lineage restriction of the RARa 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 (FDCP)–mixA4 murine progenitor cells. The major receptor expressed in undifferentiated A4 cells was RARa (primarily the RARa1 isoform). Following induction of myelomonocytic differentiation with granulocyte and granulocyte-macrophage colony-stimulating factors, a dramatic increase in RARa expression (particularly the RARa2 isoform) was seen. In contrast, expression of both RARa isoforms was rapidly extinguished upon induction of erythroid differentiation with erythropoeitin (EPO). A modest induction of RXRa expression was seen, particularly during differentiation in the myelomonocytic lineage. Low expression levels of RARg2 and RXRb remained unchanged, irrespective of differentiation pathway. Consistent with the gene expression patterns, RARa 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 RARa 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 RARa2 expression, can exert inhibitory effects on erythroid differentiation. (Blood. 2001;98:2563-2567)