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

描述（由申请人提供）：肿瘤学中一个新出现的问题是靶向肿瘤细胞的代谢状态是否可能为治疗癌症患者提供一种有希望的方法。在包括骨髓增生异常综合征（MDS）、骨髓增生性肿瘤（MPN）和急性骨髓性白血病（AML）的克隆性骨髓疾病的情况下，肿瘤起始细胞出现在造血干细胞龛中，造血干细胞龛是骨髓细胞的深度缺氧区域。 骨髓缺氧对细胞代谢有重要影响，并在正常造血干细胞的维持和功能中起着至关重要的作用。当正常造血干细胞经历致癌转化时，它们的细胞代谢发生显著变化，这可能对转化细胞如何响应低氧状态产生深远影响。然而，尚不清楚氧敏感通路在白血病细胞的增殖和存活中起什么作用。细胞中的主要氧传感器是脯氨酰羟化酶的EglN家族，其负调节HIF？（缺氧诱导因子）的活性，HIF？是一种介导细胞对缺氧反应的转录因子。有证据表明，抑制EglN可能对正常造血干细胞具有保护作用，并且可能对白血病细胞具有特别的毒性。然而，我们对正常和恶性造血细胞如何对缺氧作出反应的理解不足以确定氧敏感通路是否是骨髓恶性肿瘤的安全有效的治疗靶点。克隆性髓系疾病的治疗近年来取得了显著进展。然而，高危MDS、MPN和AML成人患者的长期生存率仍低于30%，尽管采用了包括高剂量化疗、分子靶向治疗和干细胞移植在内的强化多模式治疗。因此，非常需要针对白血病起始细胞的有效疗法。本研究假设抑制EglN可能在克隆性骨髓疾病中具有抗白血病作用，同时保护正常造血。本研究的长期目标是了解EglN活性和HIF稳定性的扰动如何影响正常和恶性造血干细胞的功能。具体而言，该研究提出使用体外转化试验以及正常造血和克隆性骨髓疾病的体内小鼠模型来表征EglN和HIF？的激活和抑制对造血细胞生长，存活和分化的影响。这项工作产生的发现将为我们理解调节正常和恶性造血的分子机制提供重要见解，这对于设计新的安全有效的治疗急性白血病和其他克隆性骨髓疾病的疗法至关重要。

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.