The aryl hydrocarbon receptor: Regulation of hematopoiesis and involvement in the progression of blood diseases

Department of Environmental Medicine, University of Rochester School of Medicine, 601 Elmwood Avenue, Box EHSC, Rochester, NY 14642, USA.
Blood Cells Molecules and Diseases (Impact Factor: 2.65). 02/2010; 44(4):199-206. DOI: 10.1016/j.bcmd.2010.01.005
Source: PubMed


The aryl hydrocarbon receptor (AhR) is a basic helix-loop-helix protein that belongs to the superfamily of environment-sensing PAS (Per-ARNT-Sim) proteins. A large number of ligands have been described to bind AhR and promote its nuclear translocation. In the nucleus, the AhR and its dimerization partner the AhR nuclear translocator (ARNT) form a DNA-binding complex that acts as a transcriptional regulator. Animal and human data suggest that, beyond its mediating responses to xenobiotic and/or unknown endogenous ligands, the AhR has a role, although as yet undefined, in the regulation of cell cycle and inflammation. The AhR also appears to regulate the hematopoietic and immune systems during development and adult life in a cell-specific manner. While accidental exposure to xenobiotic AhR ligands has been associated with leukemia in humans, the specific mechanisms of AhR involvement are still not completely understood. However, recent data are consistent with a functional role of the AhR in the maintenance of hematopoietic stem and/or progenitor cells (HSCs/HPCs). Studies highlighting AhR regulation of HSCs/HPCs provide a rational framework to understand their biology, a role of the AhR in hematopoietic diseases, and a means to develop interventions for these diseases.

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    • "Several studies indicate that murine and human HSC express modest AhR levels [98–100] and recent breakthrough studies indicate that the AhR plays a critical role in HSC growth and differentiation [95, 101–105]. For example, in vivo AhR modulation disrupts HSC growth, senescence, and migration [95, 101–103, 106, 107]. Of note is that most of these studies used environmental AhR ligands as probes to establish the nominal function of the AhR in HSCs [101, 102, 104, 106, 107]. "
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    Seminars in Immunopathology 08/2013; 35(6). DOI:10.1007/s00281-013-0390-8 · 7.75 Impact Factor
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    • "AhR participates in NF-κB signalling pathways regulating inflammation , immune responses, apoptosis, survival, and probably other functions. This aspect of biological roles of AhR is not clearly described and well known (Kung et al., 2009; Puga et al., 2009; Casado et al., 2010; Quintana & Sherr 2013; Nguyen 2013). A toxic potential of a chemical is related to its initial interaction with the target cell plasma membrane. "
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    • "The mechanisms by which AHR ligands, both exogenous and endogenous, affect these processes are poorly understood but appear to involve multiple interactions between AHR and other signaling pathways. It also is apparent that modulation of AHR via certain agonists and antagonists likely impinges on the pathophysiology of human disease states, such as cardiovascular diseases (Zhang et al., 2010), diabetes (Kerkvliet et al., 2009), cancer (Dietrich and Kaina, 2010), and blood diseases (Casado et al., 2010). Thus, selective pharmacological tools are needed to identify the various roles of AHR ligands, to assess the impact of AHR modulation in preclinical animal models of human diseases, and to determine whether AHR is an appropriate target for novel therapies. "
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