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

Abstract

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.

Figure 1

Multiple molecular interactions of the AhR with transcription factors involved in cellular responses to environmental stimuli. AhR, aryl hydrocarbon receptor; ARNT, Aryl hydrocarbon nuclear translocator; Rb, retinoblastoma tumor suppressor protein; HIF1α, hypoxia-inducible factor-1 alpha.

Figure 2

Summary of the HSC/HPC populations that might be regulated by AhR. (A) During healthy hematopoiesis, HSCs provide HPCs that will differentiate and repopulate all the lineages present in blood, (B) Dysregulation of AhR in HSCs may be carried on to HPCs and mature lineages, (C) Generation of leukemic stem cells with self-renewal properties may cause accumulation of progenitors and block differentiation into the different lineages, (D) Stem-cell exhaustion may result in reduced numbers of mature cells, (E) Disruption of the interactions between HSCs and their microenvironment may alter the homeostatic mechanisms responsible of supporting hematopoiesis. HSCs, hematopoietic stem cells; HPCs, hematopoietic progenitor cells; AhR, aryl hydrocarbon receptor.