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(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前途的方法。在克隆性髓系疾病中，包括骨髓增生异常综合征(MDS)、骨髓增生性肿瘤(MPN)和急性髓系白血病(AML)，肿瘤起始细胞出现在造血干细胞巢中，这是骨髓细胞极度缺氧的区域。 骨髓。低氧对细胞代谢有重要影响，在正常造血干细胞的维持和功能中起着至关重要的作用。当正常的造血干细胞经历致癌转化时，它们的细胞代谢发生了巨大的变化，这可能会对转化的细胞对低氧状态的反应产生深远的影响。然而，目前还不知道氧气感应通路在白血病细胞的增殖和存活中扮演着什么角色，如果有的话。细胞中的主要氧感受器是EglN家族的Pro羟基酶，它负向调节HIF(缺氧诱导因子)的活性，HIF是一种转录因子，介导细胞对缺氧的反应。有证据表明，抑制EglN可能对正常的造血干细胞具有保护作用，可能对白血病细胞特别有毒性。然而，我们对正常和恶性造血细胞对低氧的反应的了解还不足以确定氧感应通路是否会成为髓系恶性肿瘤的安全和有效的治疗靶点。近年来，克隆性髓系疾病的治疗取得了显著进展。然而，尽管包括大剂量化疗、分子靶向治疗和干细胞移植在内的强化多模式治疗，患有高危MDS、MPN和AML的成人患者的长期存活率仍不到30%。因此，非常需要针对白血病启动细胞的有效治疗方法。这项研究假设，抑制EglN可能在保护正常造血的同时，对克隆性髓系疾病具有抗白血病作用。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。具体地说，这项研究提出了利用体外转化试验以及正常造血和克隆性髓系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。这一努力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的见解，这将是设计新的安全有效的治疗急性白血病和其他克隆性髓系疾病的关键。