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) 易位产生的融合蛋白 AML 1/ETO (AE) 是一种白血病起始转录因子，通常与急性髓系白血病 (AML) 相关。尽管被定义为 AML 的“有利”亚型，但许多 AE 阳性 (AE+) 患者会复发并死于很大程度上未知的原因。目前还不清楚 AE 如何介导疾病可预测的 DNA 甲基化特征。长期目标是进一步阐明AE+AML白血病发生机制，发现新的治疗靶点并开发有效的靶向治疗。该提案的目的是探索 AE+ AML 背后的疾病可预测 DNA 甲基化特征的分子基础，重点关注缺氧独立的 HIF1α-DNMT3a 信号轴激活的影响。该提议的基本原理是，不依赖缺氧的 HIF1α 信号激活是癌症的一个新标志。就该项目而言，高度活跃的 HIF1α 信号传导可能是 AE+ AML 中的疾病促进因素和表观遗传介质。 HIF1alpha 与 AE 形成前馈环，并反式激活 DNMT3a（AE+ AML 中的另一个预后标志物）。 HIF1α 抑制可抑制 AML 细胞生长。然而，HIF1α 信号传导与 AE AML 发病机制和疾病复发之间的详细机制和生化联系尚不清楚。核心假设是，HIF1α 通过增强 AE 转录活性和调节 AML 细胞中 AE 控制的 DNA 甲基化景观来促进 AE 致白血病性。因此，HIF1α 可能是 AE+ AML 中易受攻击且可药物治疗的靶点。这一假设将通过追求三个具体目标来检验：1.) 剖析 HIF1alpha 如何对 AE 驱动的白血病发生至关重要的机制细节； 2）确定HIF1α在AE依赖的DNA甲基化中的作用； 3) 测试 HIF1alpha 的药理学靶向作为 AE+ AML 的治疗选择。为了实现我们的目标，我们将创新地将生物技术与独特的转基因和患者来源的异种移植 (POX) 小鼠模型相结合，以及异常 HIF1α 信号传导和表观遗传学的创新整合，以理解和治疗 AE+ AML。拟议的研究意义重大，因为它将揭示 AE 致白血病所需的新基因/机制途径，确定治疗生物标志物，并发现 AE+ AML 的新药物。此外，它将彻底研究 HIF1α 在癌症中的表观遗传和致癌作用。最接近的预期结果是证明 HIF1α-表观遗传学串扰在定义 AE 启动的转录调控和白血病发病机制中，并确定使用 HIF1α 抑制剂提高现有治疗方案的治疗指数的可行性。这些结果将产生重要影响，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氧独立 HIF1α 信号传导的致癌功能的理解。研究结果还将为制定更好地针对 AE+ AML 的新策略奠定基础。