The Role of EglN1 and HIF in Normal Hematopoiesis and in Leukemia

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DESCRIPTION (provided by applicant): An emerging question in oncology is whether targeting the metabolic state of tumor cells may present a promising approach to treating patients with cancer. In the case of clonal myeloid disorders, which include Myelodysplastic Syndrome (MDS), Myeloproliferative Neoplasms (MPN) and Acute Myeloid Leukemia (AML), tumor-initiating cells arise in the hematopoietic stem cell niche, a profoundly hypoxic area of the bone marrow. Hypoxia has important effects on cellular metabolism and appears to play a crucial role in the maintenance and function of normal hematopoietic stem cells. When normal hematopoietic stem cells undergo oncogenic transformation their cellular metabolism changes dramatically, which could have profound effects on how transformed cells respond to low oxygen states. However, it is not known what role, if any, oxygen-sensing pathways play in the proliferation and survival of leukemia cells. The principal oxygen sensors in cells are the EglN family of prolyl hydroxylases, which negatively regulate the activity of HIF¿ (Hypoxia Inducible Factor), a transcription factor that mediates the cellular response to hypoxia. There is evidence to suggest that inhibition of EglN may have protective effects on normal hematopoietic stem cells and may be especially toxic to leukemia cells. However, our understanding of how normal and malignant hematopoietic cells respond to hypoxia is insufficient to determine whether the oxygen-sensing pathway would be a safe and effective therapeutic target in myeloid malignancies. Therapy for clonal myeloid disorders has advanced significantly in recent years. However, the long-term survival rate of adult patients with high-risk MDS, MPN and AML is still less than 30%, despite intensive multi-modality treatments that include high-dose chemotherapy, molecularly targeted therapies and stem cell transplantation. Effective therapies that target leukemia-initiating cells are therefore very much needed. This study hypothesizes that inhibition of EglN may have anti-leukemic effects in clonal myeloid disorders while protecting normal hematopoiesis. The long-term objective of this study is to understand how perturbations in EglN activity and HIF stability affect the function of normal and malignant hematopoietic stem cells. Specifically, the research proposed uses in vitro transformation assays, as well as in vivo mouse models of normal hematopoiesis and clonal myeloid disorders, to characterize the effects of activation and inhibition of EglN and HIF¿ on hematopoietic cell growth, survival and differentiation. The discoveries generated from this effort will provide important insights into our understanding of the molecular mechanisms that regulate normal and malignant hematopoiesis, which will be critical for devising novel safe and effective therapies to treat acute leukemia and other clonal myeloid disorders.