Lineage restriction of the RAR alpha gene expression in myeloid differentiation

To better understand the role of retinoids in myelopoiesis, expression of t he retinoid receptor genes (retinoic acid receptors [RARs] and retinoid X r eceptors [RXRs]) were examined during differentiation of factor-dependent c ell-Paterson (FRCP)-mixA4 murine progenitor cells. The major receptor expre ssed in undifferentiated A4 cells was RAR alpha (primarily the RAR alpha1 i soform). Following induction of myelomonocytic differentiation with granulo cyte and granulocyte-macrophage colony-stimulating factors, a dramatic incr ease in RARa expression (particularly the RAR alpha2 isoform) was seen. In contrast, expression of both RAR alpha isoforms was rapidly extinguished up on induction of erythroid differentiation with erythropoeitin (EPO). A mode st induction of RXR alpha expression was seen, particularly during differen tiation in the myelomonocytic lineage. Low expression levels of RAR gamma2 and RXR beta remained unchanged, irrespective of differentiation pathway. C onsistent with the gene expression patterns, RAR alpha agonists and antagon ists stimulated myelomonocytic and erythroid differentiation of FDCP-mixA4 cells, respectively. Taken together, these results suggest that erythropoie sis and granulopoiesis require diminished and enhanced RAR alpha activities , respectively, which at physiological all-trans-retinoic acid (RA) concent rations 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 exer t: inhibitory effects on erythroid differentiation. (Blood. 2001;98:2563-25 67) (C) 2001 by The American Society of Hematology.