Unrestricted A20 activity in acute myeloid leukemia

急性髓系白血病中 A20 活性不受限制

• 批准号: 9755096
• 负责人: Ashley Elizabeth Cochran
• 金额: $ 7.04万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755096
• 关键词: Acute Myelocytic Leukemia; Address; Age; Anemia; Automobile Driving; Biological Assay; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Cleaved cell; Clonal Hematopoietic Stem Cell; Complex; Development; Disease; Electron Microscopy; Enzymes; Epigenetic Process; Event; FLT3 gene; Frequencies; Functional disorder; Future; Genetic; Goals; Hematopoiesis; Hematopoietic stem cells; Immune response; Immunoblotting; Impairment; In Vitro; Individual; Infection; Interruption; Knock-out; Knockout Mice; Leukemic Cell; Life Expectancy; Link; Lymphoid; Lysine; MLL-AF9; Malignant - descriptor; Mediating; Modeling; Molecular; Morphology; Mus; Mutation; Myelogenous; Myeloid Leukemia; Myeloid Progenitor Cells; Myeloproliferative disease; NF-kappa B; Necrosis; Oncogenes; Pathogenesis; Patients; Phenotype; Population; Predisposition; Prevalence; Property; Proteins; RIPK1 gene; RIPK3 gene; RUNX1 gene; Research; Role; Signal Transduction; Taxes; Testing; Ubiquitin; acute myeloid leukemia cell; base; cancer cell; chemotherapeutic agent; chemotherapy; clinically relevant; defined contribution; design; experimental study; fitness; fundamental research; immune system function; immunoregulation; in vivo; inhibitor/antagonist; leukemia; leukemic stem cell; leukemogenesis; mouse model; mutant; novel; novel therapeutics; overexpression; peripheral blood; prevent; progenitor; self-renewal; therapeutic target; therapy development; ubiquitin-protein ligase

Project Summary A20, or TNFAIP3, is a unique dual-function enzyme that is capable of both adding and cleaving ubiquitin chains from target proteins. Ubiquitin chains are essential for intracellular signaling. Specifically, A20’s ubiquitin editing activity is responsible for negative regulation of immune responses and programmed necrosis by restricting NF-kB signaling and RIP signaling, respectively. Inactivating mutations of A20 are associated with lymphoid disorders. Somewhat unexpectedly, however, we have determined that acquired A20 function may be involved in acute myeloid leukemia (AML). AML is characterized by a block in differentiation and acquired self-renewal properties of myeloid progenitor cells, leading to an accumulation of blasts in the bone marrow resulting in anemia, increased susceptibility to infection, and, if untreated, death. While it can occur at any age, it is most common in those over age 60, with prevalence of the diseased expected to increase as the life expectancy of the population increases. Current treatment options include chemotherapy and/or bone marrow transplant, both of which can be taxing even for an otherwise healthy, young individual. A complex interplay of genetic and epigenetic events contributes to the pathogenesis of AML. Despite a better understanding of the mechanisms of AML pathogenesis, new therapy development and identification of therapeutic targets has been limited. From our preliminary findings, A20 is frequently overexpressed in blasts of AML patients and elevated A20 levels in AML patients correlate with a shorter overall survival. Moreover, deletion of A20 in leukemic mouse bone marrow cells impairs leukemic cell function in vitro and prolongs survival in a mouse model of AML. Importantly, the effects of A20 loss were nominal in healthy mouse bone marrow. Furthermore, knockout of A20 in leukemic cells resulted in necrotic signaling and morphology as evidenced by immunoblotting and electron microscopy, respectively, and cell death was rescued by treatment with a necrosis inhibitor. Based on these findings, we predict that A20 contributes to the persistence of leukemic cells through inhibition of an alternative form of cell death, programmed necrosis. Our long-term goal is to understand the mechanisms driving AML development. While A20 has well characterized roles in the immune system, the function of A20 in myeloid leukemia remains unclear. The objectives of this study are (1) to assess A20 function in leukemic stem cells, and (2) to pinpoint the essential ubiquitin-editing function of A20 involved in the pathogenesis of AML. Thus, the proposed project seeks to address a fundamental gap in AML research. In doing so, we will test the following, central hypothesis: Overexpression of A20 in AML assists malignant cells in evading cell death by preventing programmed necrosis. Together, the proposed studies seek to reveal A20’s involvement in the initiation and progression of AML, thereby determining the potential of A20 as a therapeutic target for AML.

项目概要 A20 或 TNFAIP3 是一种独特的双功能酶，能够添加和切割泛素 来自目标蛋白质的链。泛素链对于细胞内信号传导至关重要。具体来说，A20 的泛素 编辑活动负责免疫反应和程序性坏死的负调节 分别限制 NF-kB 信令和 RIP 信令。 A20 的失活突变与 淋巴系统疾病。然而有些出乎意料的是，我们确定获得的 A20 功能可能 参与急性髓系白血病（AML）。 AML 的特点是骨髓细胞分化受阻并获得自我更新特性 祖细胞增加，导致骨髓中原始细胞积聚，导致贫血 易受感染，如果不治疗，甚至会死亡。虽然它可以发生在任何年龄，但最常见于那些 60岁以上，随着人口预期寿命的延长，患病率预计会增加 增加。目前的治疗选择包括化疗和/或骨髓移植，这两种方法都可以 即使对于一个健康的年轻人来说，这也是一种负担。遗传和表观遗传事件的复杂相互作用 有助于 AML 的发病机制。尽管人们对 AML 的机制有了更好的了解 发病机制、新疗法的开发和治疗靶点的确定受到限制。 根据我们的初步发现，A20 在 AML 患者的原始细胞中经常过度表达，并且 A20 升高 AML 患者的水平与较短的总生存期相关。此外，白血病小鼠中 A20 缺失 骨髓细胞在体外损害白血病细胞功能并延长 AML 小鼠模型的生存期。 重要的是，A20 损失对健康小鼠骨髓的影响是微不足道的。此外，淘汰赛 免疫印迹和免疫印迹证明，白血病细胞中的 A20 导致坏死信号传导和形态学。 分别用电子显微镜观察，细胞死亡通过坏死抑制剂治疗得以挽救。基于 根据这些发现，我们预测 A20 通过抑制 细胞死亡的另一种形式，程序性坏死。 我们的长期目标是了解驱动 AML 发展的机制。虽然A20有很好的 尽管 A20 在免疫系统中的作用已得到证实，但 A20 在骨髓性白血病中的功能仍不清楚。这 本研究的目标是 (1) 评估白血病干细胞中的 A20 功能，以及 (2) 查明关键的 A20 的泛素编辑功能参与 AML 的发病机制。因此，拟议项目旨在 解决 AML 研究的根本差距。在此过程中，我们将检验以下中心假设： AML 中 A20 的过度表达可通过阻止程序性细胞死亡来帮助恶性细胞逃避细胞死亡。 坏死。总之，拟议的研究旨在揭示 A20 参与的启动和进展 AML，从而确定 A20 作为 AML 治疗靶点的潜力。