Human exposures to polycyclic aromtic hydrocarbons and dioxins have been linked to the development of lymphomas and leukemias. The actions of these chemicals are mediated by a gene regulatory protein, the aryl hydrocarbon receptor (AhR). Persistent AhR activation in mice results in altered numbers and function of hematopoietic stem cells (HSCs). Preliminary data from Ahr null-allele (AhR-KO) mice also provides evidence to indicate that the AhR has a physiological role in the regulation of HSCs. The overall hypothesis is that AhR dysregulation plays a role in a number of hematopoietic disorders including leukemia. In this proposal we will begin to test the specific hypothesis that the AhR has an important role in the self-renewal and proliferation of HSCs. To do this, it is necessary to further define the phenotypic and functional characteristics of HSCs in AhR-KO mice. Using this mouse model and a variety of flow cytometry approaches, we will determine if HSCs in AhR-KO mice have high proliferation rates in vivo, and will identify the specific phenotypically-defined cell populations exhibiting this characteristic. We will also define the multi-lineage developmental potential of these cells under hematopoietic stress conditions. In a second aim, we will assess by primary and serial transplantation, the ability and kinetics of HSCs from AhR-KO mice for multi-lineage reconstitution.
The further understanding of the processes regulating HSC self-renewal and differentiation are fundamental to the prevention and treatment of a variety of leukemias and other hematopoietic diseases in humans. Understanding what regulates the normally incredible regenerative capacity of bone marrow also has clinical implications for bone marrow transplantation, autoimmune disease, and bone marrow failure that may be associated with cancer treatment. Furthermore, these events are intimately tied with the process of aging and a variety of diseases, including cancer, whose incidence increases with age.
