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

EglN1 和 HIF 在正常造血和白血病中的作用

• 批准号: 8915102
• 负责人: Julie Aurore Losman
• 金额: $ 17.67万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-20 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915102
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Adult; Affect; Anemia; Antineoplastic Agents; Area; Biological Assay; Bone Marrow; Cell Differentiation process; Cell Line; Cells; Characteristics; Clinical Treatment; Clinical Trials; Combined Modality Therapy; Complementary DNA; Disease; Disease Progression; Dominant-Negative Mutation; Dysmyelopoietic Syndromes; Family; Goals; Growth; Growth Factor; Health; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; High Dose Chemotherapy; Human; Hypoxia; Hypoxia Inducible Factor; In Vitro; Link; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Modality; Molecular; Mutation; Myelogenous; Myeloid Leukemia; Myeloproliferative disease; Oncogenes; Oncogenic; Oxygen; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Procollagen-Proline Dioxygenase; RNA Interference; Research; Role; Stem cell transplant; Survival Rate; Tissues; Tumor Suppressor Genes; Tumor Suppressor Proteins; Up-Regulation; Work; alpha ketoglutarate; base; cancer therapy; cell growth; cell transformation; cytokine; design; effective therapy; enantiomer; high risk; hypoxia inducible factor 1; in vivo; inhibitor/antagonist; insight; leukemia; leukemogenesis; mortality; mouse model; mutant; neoplastic cell; novel; oncology; overexpression; protective effect; response; self-renewal; sensor; stem cell niche; targeted treatment; therapeutic target; transcription factor; tumor

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.

描述（由申请人提供）：肿瘤学中的一个新问题是，在克隆性骨髓疾病（包括骨髓增生异常综合征（MDS）、骨髓增生性肿瘤）的情况下，针对肿瘤细胞的代谢状态是否可能成为治疗癌症患者的一种有前途的方法。 （MPN）和急性髓系白血病（AML）中，肿瘤起始细胞出现在造血干细胞生态位中，这是造血干细胞的一个严重缺氧的区域。这 骨髓缺氧对细胞代谢有重要影响，并且似乎在正常造血干细胞的维持和功能中发挥着至关重要的作用。然而，目前尚不清楚氧传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 EglN 家族。脯氨酰羟化酶，负向调节 HIF 的活性（缺氧诱导因子），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。正常和恶性造血细胞对缺氧的反应不足以确定氧传感通路是否是骨髓恶性肿瘤治疗中安全有效的治疗靶点。近年来，骨髓疾病取得了显着进展，尽管采用了包括大剂量化疗、分子化疗在内的强化多模式治疗，但患有高危 MDS、MPN 和 AML 的成年患者的长期生存率仍然低于 30%。因此，非常需要针对白血病起始细胞的有效疗法，该研究表明抑制 EglN 可能在克隆性骨髓疾病中具有抗白血病作用，同时保护正常细胞。这项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。具体来说，该研究建议使用体外转化测定以及体内小鼠模型。正常造血和克隆性骨髓疾病的研究，以表征 EglN 和 HIF 激活和抑制的影响。这项工作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的见解，这对于设计治疗急性白血病和其他疾病的新型安全有效的疗法至关重要。克隆性骨髓疾病。