The role of retinoids and retinoic acid receptors in normal hematopoiesis

Abstract

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.

All-trans-retinoic Acid Promotes Iodine Uptake Via Up-regulating the Sodium Iodide Symporter in Medullary Thyroid Cancer Stem Cells

“…Cancer stem cells (CSCs) are thought to represent a small sub-population of cells presented in most tumors, possess the ability to self-renew, proliferate and produce progenitor cells that can reconstitute and sustain tumor growth (Collins, 2002;Christina Zechel, 2005;Rashidi et al, 2013). Moreover, CSCs also play a key role in cancer metastasis, cancer recurrence, and cancer drug resistance (Hadnagy, 2006;Jordan et al, 2006;Lin, 2011).…”

Ex vivo expansion of umbilical cord blood stem cells for transplantation: growing knowledge from the hematopoietic niche

“…110,111 Copper chelation The copper chelation system utilizing tetraethylenepentamine 112-114 may also maintain a primitive phenotype, murine models have shown improved engraftment, and early clinical trials of this system are underway at MD Anderson Cancer Center. 115 All-trans retinoic acid (ATRA) has been implicated in the regulation of hematopoiesis [116][117][118] and CD34 þ CD38ÀLinÀ cells from UCB cultured in a non-contact system with AFT024 stromal cells, FL and TPO, with or without ATRA showed increased LTC-IC, ML-IC and SRC expansion via a stromal cell non-contact dependent mechanism. 119 Wnt pathway activation Agents that can activate the Wnt pathway such as the glycogen synthase kinase-3 inhibitor 6-bromoindurubin-3 0 -oxime may ultimately enhance HSC repopulation.…”

Treatment by design in leukemia, a meeting report, Philadelphia, Pennsylvania, December 2002

“…25,26 RA acts as a potent differentiation agent in various hematopoietic cell types. 27 The PML-RARa fusion protein encoded by the (15;17) translocation in APL binds the promoter and acts as DN inhibitors of transcription through stable transcriptional repression. 28 The repressor complex binds to the promoter, blocking gene transcription and blocking expression of key genes involved in hematopoietic cell differentiation.…”