The Role of HIF1A-DNMT3A axis in AML1/ETO-Driven Acute MyelogenousLeukemia

HIF1A-DNMT3A 轴在 AML1/ETO 驱动的急性髓系白血病中的作用

• 批准号: 10740439
• 负责人: Shujun Liu
• 金额: $ 66.87万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-07 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740439
• 关键词: AML1-ETO fusion protein; Acute; Acute Myelocytic Leukemia; Address; Binding; Binding Sites; Biochemical; Biological; Biological Markers; Cells; Chimeric Proteins; Clinical; DNA Methylation; DNA Sequence Alteration; DNMT3a; Disease; Disease Progression; Disease remission; Environment; Epigenetic Process; Genes; Genetic Transcription; Goals; Growth; HIF1A gene; Hormones; Hyperactivity; Hypoxia; Hypoxia Inducible Factor; In Vitro; Intervention; Investigation; Leukemic Cell; Link; Literature; Malignant Neoplasms; Mediating; Mediator; Medicine; Molecular; Nature; Oncogenic; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Positioning Attribute; Prognosis; Prognostic Marker; Proteins; RUNX1 gene; Recurrence; Recurrent disease; Refractory; Relapse; Research; Role; Signal Transduction; Techniques; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Index; Time; Transcription Initiation; Transcriptional Regulation; Transgenic Mice; Transgenic Organisms; Treatment Protocols; Work; acute myeloid leukemia 1 protein; acute myeloid leukemia cell; cell growth; chemotherapy; clinical efficacy; cofactor; cytokine; driver mutation; drug testing; druggable target; improved; in vivo; inhibitor; innovation; insight; leukemia; leukemia treatment; leukemic stem cell; leukemogenesis; molecular pathology; mouse model; new therapeutic target; normoxia; novel; novel therapeutics; patient derived xenograft model; pharmacologic; predictive signature; promoter; relapse patients; response; t(8; 21)(q22; q22); targeted treatment; therapeutic biomarker; therapeutic development; therapy outcome; transcription factor

The fusion protein AML 1/ETO (AE), resulting from the t(8;21) translocation, is a leukemia-initiating transcription factor that is frequently associated with acute myeloid leukemia (AML). Despite being defined as a "favorable" subtype of AML, many AE positive (AE+) patients relapse and die with largely unknown causes. It is also unclear how AE mediates a disease-predictable DNA methylation signature. The long-term goals are to elucidate further the mechanisms of AE+ AML leukemogenesis, discover new therapeutic targets and develop effective targeted therapies. The objective of this proposal is to explore the molecular basis of a disease-predictable DNA methylation signature underlying AE+ AML with a focus on the impact of hypoxia-independent HIF1alpha-DNMT3a signaling axis activation. The rationale underlying this proposal is that the hypoxia-independent HIF1alpha signaling activation is a new hallmark of cancer. In relation to this project, the hyperactive HIF1alpha signaling may be a disease-promoting factor and an epigenetic mediator in AE+ AML. HIF1alpha forms a feedforward loop with AE and transactivates DNMT3a, another prognostic marker in AE+ AML. HIF1alpha inhibition suppresses AML cell growth. However, the detailed mechanistic and biochemical links between HIF1alpha signaling and AE AML pathogenesis and disease recurrence are poorly defined. The central hypothesis is that HIF1alpha promotes AE leukemogenicity through enhancing AE transcriptional activities and modulating the AE-governed DNA methylation landscape in AML cells; therefore HIF1alpha may be a vulnerable and druggable target in AE+ AML. This hypothesis will be tested by pursuing three specific aims: 1.) Dissect the mechanistic details of how HIF1alpha is critical for AE-driven leukemogenesis; 2) Determine the role of HIF1alpha in AE-dependent DNA methylation; 3) Test pharmacological targeting of HIF1alpha as a therapeutic option for AE+ AML. To pursue our aims, we will use innovative combinations of biological techniques with unique transgenic and patient-derived xenograft (POX) mouse models, as well as innovative integration of aberrant HIF1alpha signaling and epigenetics in understanding and treating AE+ AML. The proposed research is significant, because it will disclose new genes/mechanistic pathways that are necessary for AE leukemogenicity, identify the therapeutic biomarkers, and discover new medicinal agents for AE+ AML. Further, it will thoroughly investigate the epigenetic and oncogenic role of HIF1alpha in cancer. The proximate expected outcomes are to demonstrate HIF1alpha-epigenetics crosstalk in defining AE-initiated transcriptional regulation and leukemia pathogenesis, and to establish the feasibility of using HIF1alpha inhibitors to enhance the therapeutic index of the existing treatment regimens. The results will have an important impact because they will advance our understanding of AE+ AML molecular pathology, aberrant epigenetics in leukemia and the oncogenic functions of hypoxia-independent HIF1alpha signaling in cancers. The findings will also lay the groundwork to develop newer strategies to better target AE+ AML.

由T（8; 21）易位引起的融合蛋白AML 1/ETO（AE）是白血病发射转录因子，经常与急性髓样白血病（AML）有关。尽管被定义为AML的“有利”亚型，但许多AE阳性（AE+）患者复发，并死于未知原因。目前尚不清楚AE如何介导可预测的可预测的DNA甲基化特征。长期目标是进一步阐明AE+ AML白血病发生的机制，发现新的治疗靶标并开发有效的靶向疗法。该提案的目的是探索AE+ AML基础的可预测DNA甲基化特征的分子基础，重点是与缺氧独立的HIF1Alpha-DNMT3A信号轴激活的影响。该提议的基本原理是，与缺氧独立的HIF1Alpha信号传导激活是癌症的新标志。与该项目有关，多动性HIF1Alpha信号传导可能是促进疾病的因素和AE+ AML中的表观遗传介质。 HIF1Alpha与AE形成一个前馈环，并反式激活DNMT3A，这是AE+ AML中的另一个预后标记。 HIF1Alpha抑制抑制AML细胞的生长。但是，HIF1Alpha信号传导与AE AML发病机理和疾病复发之间的详细机械和生化联系的定义很差。中心假设是HIF1Alpha通过增强AE转录活性并调节AML细胞中的AE-Govered DNA甲基化景观来促进AE白血病性。因此，HIF1Alpha可能是AE+ AML中的脆弱且可吸毒的靶标。该假设将通过追求三个特定目的来检验：1。）剖析HIF1Alpha如何对AE驱动的白血病生成至关重要的机械细节； 2）确定HIF1Alpha在AE依赖性DNA甲基化中的作用； 3）测试HIF1Alpha作为AE+ AML的治疗选择的药理靶向。为了实现我们的目标，我们将使用独特的转基因和患者衍生的异种移植（POX）小鼠模型的生物技术的创新组合，以及异常HIF1Alpha信号和表观遗传学的创新整合，以理解和治疗AE+ AML。拟议的研究很重要，因为它将披露针对AE白血病性所必需的新基因/机械途径，识别治疗性生物标志物，并发现针对AE+ AML的新药物。此外，它将彻底研究HIF1Alpha在癌症中的表观遗传和致癌作用。预期的近端结果是在定义AE引起的转录调控和白血病发病机理方面证明HIF1Alpha- epigenetics串扰，并确定使用HIF1Alpha抑制剂以增强现有治疗方案的治疗指数的可行性。结果将产生重要的影响，因为它们将促进我们对AE+ AML分子病理学，白血病异常表观遗传学以及癌症中缺乏依赖性HIF1Alpha信号的致癌功能的理解。这些发现还将为制定更新的策略奠定基础，以更好地针对AE+ AML。