Regulation of normal and leukemic hematopoiesis by type I interferon

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DESCRIPTION (provided by applicant): The goals of this project are to define the mechanisms by which type I IFNs alter the fates of immature hematopoietic stem cells (HSCs) and progenitor cells, and to identify the effect and underlying mechanisms of type I IFNs on the health and potential of normal and leukemic HSCs. These studies will be carried out using HSCs and progenitor cells isolated from wild-type mice and from the SCLtTAxBCR/ABL double transgenic mouse model of human chronic myelogenous leukemia (CML), and a comprehensive array of in vivo and in vitro experimental approaches. In the first aim, we will investigate how short-term (days) and long-term (weeks) exposure to type I IFNs affects the biology of HSCs and progenitor cells with respect to their quiescence, proliferation, potential, and susceptibility to apoptosis. We will also examine whether chronic (months) exposure to type I IFNs damages HSC self-renewal. Lastly, we will define the molecular mechanisms underlying these changes. In the second aim, we will assess how type I IFNs affect the biology of leukemic HSCs and progenitor cells compared to wild type cells. We will investigate how the deregulated properties of BCR/ABL-expressing leukemic HSCs (i.e., increased proliferation, decreased quiescence, increase survival) change their response to type I IFNs exposure and may sensitize them to combinatorial treatments with type I IFNs and the BCR/ABL tyrosine kinase inhibitor, Imatinib. Taken together, these approaches should uncover how inflammatory signals such as type I IFNs impact on the regulatory networks that normally control HSC and progenitor cell homeostasis, and how the deregulated properties of leukemic HSCs may alter their sensitivity to the effects of inflammatory signals and therapeutic interventions. PUBLIC HEALTH RELEVANCE: This project seeks to understand how type I interferons (IFNs), a large family of inflammatory proteins, affects the biology of hematopoietic stem cells (HSCs), a small population of bone marrow cells that generate all blood cells. Improper regulation of HSC activity can lead to a number of severe blood diseases. These include chronic myelogenous leukemia (CML), which has long been treated with type I IFNs despite the lack of knowledge regarding their mechanism of action. Recent clinical work suggests that type I IFNs may enhance the curative effect of other CML treatments, such as the tyrosine kinase inhibitor Imatinib. By uncovering how type I IFNs affect the biology of normal and leukemic HSCs, and the molecular mechanisms underlying these effects, the proposed work could be of significant value to public health by providing the basis for the design of more effective co-treatments for CML and other blood diseases that will harness the beneficial effect of type I IFNs.