Adult HSCs are able to maintain homeostasis of hematopoiesis through their ability to self-renew and differentiate into HPCs while maintaining a pool of HSCs lasting throughout a lifetime. The critical function of the numerically rare HSC is exquisitely regulated by multiple intrinsic and extrinsic mechanisms [7]. HSC maintenance is intrinsically regulated by restricting proliferation [8-10] and promoting self-renewal. Self-renewal of HSCs is linked to the pathways that contribute to the commitment of cell types during development. Many of these developmental regulators act as ligands that lead to the activation of transcription factors such as GATA2, p53, retinoic acid receptor among others [11]. Stem cells are also contained within physical and chemical environments known as microenvironments or niches [12] that extrinsically regulate HSC function by releasing soluble factors [13, 14], activating intermediate cells [15-17], or by direct cell-cell interactions [18, 19].

When in the cytoplasm, AhR forms a complex with the chaperone protein heat-shock protein (Hsp)90, co-chaperone p23, and an immunophilin-like protein (AIP or XAP-2) [22]. Following ligand binding [23], the AhR amino (N)-terminal nuclear localization signal is activated directing it to translocate to the nucleus. Once in the nucleus, AhR forms a heterodimeric complex with the aryl hydrocarbon nuclear translocator (ARNT; also known as HIF-1β). The AhR-ARNT complex binds to a consensus core DNA recognition sequence 5′-TNGCGTG-3′ known as the AhR responsive element (AhRE) [24]. The AhR also contains a glutamine-rich transactivation domain in its carboxy (C)-terminal region which participates in the AhR-ARNT mediated recruitment of coactivators, co-repressors and basal transcription factors [25]. The AhR-ARNT heterodimer has been shown to regulate the expression of several batteries of genes involved in diverse signaling pathways including phase I/II metabolism, inflammation, and cell cycling [26]. However, the exact normal function of this transcription factor has not yet been defined.

The AhR was discovered as the mediator of the toxic responses of halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons (PAHs), including the most potent 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, it is now known that a range of structurally diverse xenobiotic chemicals can bind the AhR with different affinities [24, 27]. Most of these compounds are potent inducers of several drug-metabolizing enzymes – particularly, CYP1a1, CYP1a2 and CYP1b1 – glutathione-S-transferase Ya and NAD(P)H-quinone oxidoreductase. Interestingly, there are several endogenous compounds capable of AhR-mediated induction of these genes such as tryptamine, indole acetic acid, bilirubin, biliverdin, 2-(10H-indole-30-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), tryptophan metabolites including the photoproduct 6-formylindolo[3,2-b]carbazole (FICZ), lipoxin A4 [27, 28], leukotriene A4 derivatives [29] and the intracellular second messenger cAMP [30]. However, the true endogenous ligands have not yet been clearly identified.

Due to the discovery of the AhR in association with the toxic dioxins [31], and the limited information about the existence or identity of AhR endogenous ligands [22], much of what is known about AhR biology is based on activation of the receptor using exogenous chemicals. TCDD, the most potent exogenous AhR ligand, and other dioxins are by-products of the chemical synthesis of herbicides popularly used between 1960 and 1980. These chemicals are also contaminants formed during several manufacturing processes and during the incineration and combustion of waste materials. As such, they are still relatively ubiquitous, but most often found at higher concentrations in areas near manufacturing plants and incineration sites where they could be released. Because they are highly lipophilic and bioaccumulate; dioxins are environmental pollutants found in the human food chain [32]. As endocrine disruptors, dioxins have been found to alter reproductive behavior in wildlife and laboratory animals [33], and have been shown to be potent carcinogens for multiple end-points [34]. In humans, dioxins are carcinogenic [34] and immunotoxic [35]. Benzo[a]pyrene (BP), another PAH and AhR ligand, is also found in tobacco and coal smoke. However, metabolites of BP, produced by enzymes transcriptionally regulated by the AhR, can also form DNA-binding adducts and cause mutagenesis and other effects by non-AhR pathways [36].

Besides the transcriptional activation through AhRE DNA binding, there is also evidence to suggest that ligand binding to AhR can elicit biological responses through AhR interactions with other transcription factors or cofactors. In an in vivo ischemia-induced model, treatment with BP was shown to impair angiogenesis by a molecular mechanism that results in induced vascular endothelial growth factor (VEGF). The proposed mechanism suggests that after ligand binding the formation of the AhR-ARNT complex resulted in lower levels of ARNT bound to its other partner HIF-1α whose signaling resulted in upregulation of VEGF [36]. More recently, AhR deficiency has also been shown to modulate angiogenesis by a mechanism involving VEGF depletion in endothelial cells and overexpression of TGF-β in stromal cells [37]. In mammary tumor cells, the association between the RelA subunit of NFκB and AhR induced cellular proliferation by activation of the oncogene c-myc [38, 39]. Also, interactions between AhR and the RelB subunit of NFκB induced chemokine production in leukemic cells [40]. In the lung, AhR appears to have a role in regulating inflammatory responses by maintaining RelB expression in fibroblasts [41]. AhR interaction with Rb has been shown to suppress progression of the S-phase of the cell cycle, but this interaction is restricted to the hypophosphorylated form of Rb found in quiescent cells, suggesting that the AhR is a negative regulator of proliferation [42, 43]. Alternatively, the AhR-Rb interaction has been proposed to coactivate the transcription of genes encoding proteins that suppress cell cycle progression in hepatoma cells [44]. Together these data suggest that while there are multiple mechanisms for AhR regulation of several signaling pathways, in particular those involving the cell cycle, the responses are specific to the type and cycling status of the cell.

AhR-mediated responses to cellular stress by mechanisms specific to cell type have also been proposed. Part of the short- and long-term cellular stress responses of skin to ultraviolet light, including altered cell cycling and inflammatory reactions, may be mediated by AhR ligands generated as photoproducts [45]. Acute-phase response genes regulated by NF-κB are expressed in hepatocytes as an early reaction to cellular stress, and AhR ligands have been shown to repress this response in murine and human hepatocytes by a mechanism that requires AhR-ARNT nuclear translocation but not AhRE binding [46]. In response to light, TCDD also alters expression of the circadian regulators Per1 and Bmal1 genes and changes the phase shifts of circadian-regulated responses [47]. AhR and cyp1a1 genes have been shown to have a circadian expression in hepatocytes, brain cells [47] and immune cells [48]. These data support the concept that the AhR participates in the regulation of responses to environmental stimuli. Figure 1 illustrates these mechanisms emphasizing that AhR actions involve direct interaction of the AhR-ARNT complex with DNA through AhREs and/or interactions of the AhR with other transcription factors. Note that the ultimate responses observed following altered AhR activity may not be mutually exclusive to specific mechanisms. For example, the involvement of the AhR to regulate cell cycle may occur by mechanisms other than its ability to interact with Rb.

Functional AhR is expressed by different hematopoietic and immune populations. In B-cells, the constitutive low levels of AhR mRNA and protein expression are highly upregulated after activation of resting cells [60, 6]. Western blots of human monocytes and CD34⁺ progenitors showed constitutive levels of the protein [61, 62]. When CD4⁺ T-cells become activated, the level of AhR message is upregulated in Th17 populations [55, 63]. AhR expression can also be detected in certain bone marrow stromal cell lines [64] and some cell lines derived from leukemic cells [65]. AhR message has been detected in murine LSK cells [6, 66].

Despite AhR being ubiquitous in the hematopoietic and immune system, the type and the magnitude of the responses initiated by AhR-activation appears to be cell-specific [67]. In macrophages, AhR interacts with signal transducer and activator of transcription 1 (Stat1) and NFκB to regulate proinflammatory innate immune responses elicited by LPS [57]. Dendritic cells that present antigen to naïve T cells in the periphery are reduced in numbers after AhR activation by the low-molecular-weight compound VAF347, and this appears to be due to the AhR-dependent decreased expression of IL6, IL10 and TGFβ [68]. During Th17 cell development, AhR regulates differentiation via Stat1, and AhR activation upregulates secretion of the inflammatory cytokines IL17 and IL22 [55]. Regulatory T-cells (Treg) inhibit cell proliferation of effector cells and cytokine secretion to suppress immune responses after they have been mounted. Ligand-mediated AhR activation increases Treg proliferation while suppressing experimental autoimmune encephalitis [63] and preventing graft-versus-host disease [69, 70].

Thymic atrophy has been recognized as a hallmark of exposure to the xenobiotic AhR agonist TCDD. As such, much effort has been devoted to understanding the mechanisms responsible and the role of the AhR functioning as a transcription factor in the hematopoiesis, and lymphopoiesis in particular. Studies using AhR-chimeric mice have shown that thymocytes and/or thymocyte precursors need to express AhR in order for TCDD or other dioxin-like xenobiotics to elicit this particular toxic effect [71], suggesting that the persistent activation by TCDD is disrupting some normal role of the AhR in these cells. There is evidence supporting TCDD-elicited reduced seeding of the thymus by bone marrow-derived progenitors [72], reduced stromal-mediated proliferation of thymocytes [73, 74] and a skewing of the thymic output through direct effects on developing thymocytes [75]. Additionally, it has been shown that AhR activation during gestation leads to alterations of B lineage cells with possible consequences on autoimmunity [76].

At least at present, there are few Ahr gene polymorphisms known to be associated with human cancers. Several of these are associated with lung and upper intestinal tract cancer and appear to be related to the ability of the AhR to regulate the expression of enzymes responsible for the metabolism of several xenobiotics, in particular the PAHs [80-83]. One of the most studied Ahr polymorphisms in humans, G1661A, where a lysine residue at amino acid 544 replaces an arginine, has also been associated with DNA damage in peripheral lymphocytes of coke-oven workers occupationally exposed to PAHs [84]. In a recent study, a particular Ahr polymorphism, in conjunction with exposure to organochlorines, was also associated with increasing risk of non-Hodgkin lymphoma [85]. There is at present no known association between any Ahr polymorphism and increased incidence of any hematopoietic disease or cancers in the absence of known xenobiotic exposures. However, there have been few, if any, studies to examine for these associations.

Based on the evidence for different mechanisms recognized to disrupt HSC functions and lead to hematopoietic diseases, along with evidence supporting a role of the AhAR in the regulation of HSCs, we propose that AhR involvement in these diseases may occur through (a) dysregulation of AhR signaling in HSCs/HPCs, (b) generation of leukemic stem cells, (c) depletion of the stem cell compartment, and/or (d) disruption of HSC-microenvironment interactions. This hypothesis is based on the following evidence as summarized in Table 2: