The role of retinoids and retinoic acid receptors in normal hematopoiesis

The dramatic therapeutic activity of all-trans retinoic acid (ATRA) in inducing terminal granulocytic differentiation of the malignant promyelocytes that characterize human acute promyelocytic leukemia (APL) has led to numerous studies assessing the role of retinoids and the retinoic acid receptors (RARs) in the regulation of normal hematopoiesis. Studies with knock out mice indicate that retinoic acid receptor activity is not essential for normal hematopoiesis, but both in vitro and in vivo studies indicate that these receptors may be important modifiers/regulators of different myeloid precursors/progenitors including the primitive transplantable stem cell. A number of target genes have been identified that are either directly or indirectly regulated by RA receptors and which likely play important roles in the retinoid-mediated regulation of myelopoiesis. Several in vitro models of hematopoiesis suggest that the transcriptional activity of RA receptors is developmentally regulated during different stages of myelopoiesis. This regulation might involve non-ligand mediated molecular events that alter the interaction of RA receptors with transcriptional corepressor complexes. Moreover, the interaction of RA receptors with other families of transcription factors expressed in different hematopoietic lineages might also account for differential RA receptor activity at different stages of myelopoiesis.