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.

项目摘要 A20或TNFAIP3是一种独特的双功能酶，能够添加和裂解泛素 靶蛋白的链。泛素链对于细胞内信号传导至关重要。具体来说，A20的泛素 编辑活动负责免疫复杂和通过 分别限制NF-KB信号传导和RIP信号传导。 A20的灭活突变与 淋巴疾病。但是，出乎意料的是，我们已经确定获得的A20功能可能 参与急性髓样白血病（AML）。 AML的特征是分化的块和髓样的自我更新特性 祖细胞导致骨髓中爆炸的积累，导致贫血，增加了 感染的敏感性，如果未经治疗，则死亡。虽然它可以在任何年龄发生，但最常见 60岁以上，随着人口的预期寿命，被裁员的普遍性预计会增加 增加。当前的治疗选择包括化学疗法和/或骨髓移植，这两者都可以 即使对原本健康的年轻人也要征税。遗传和表观遗传事件的复杂相互作用 有助于AML的发病机理。尽管对AML的机制有了更好的了解 发病机理，新的治疗发展和治疗靶标的鉴定受到限制。 从我们的初步发现，A20在AML患者的爆炸中经常过表达并升高A20 AML患者的水平与较短的总生存期相关。此外，在白血病鼠标中删除A20 骨髓细胞会在体外损害白血病细胞的功能，并在AML小鼠模型中延长生存率。 重要的是，在健康的小鼠骨髓中，A20损失的影响是名义的。此外，淘汰 白血病细胞中的A20导致坏死信号传导和形态，这是通过免疫印迹和 通过用坏死抑制剂治疗挽救电子显微镜和细胞死亡。基于 这些发现，我们预测A20通过抑制A20有助于白血病细胞的持久性 细胞死亡的替代形式，编程坏死。 我们的长期目标是了解推动AML开发的机制。虽然A20很好 在免疫系统中的表征作用，A20在髓样白血病中的功能尚不清楚。这 这项研究的目标是（1）评估白血病干细胞中的A20功能，（2）查明必需品 A20的泛素编辑功能参与AML的发病机理。那是拟议的项目试图 解决AML研究中的基本差距。通过这样做，我们将测试以下中心假设： AML中A20的过表达通过防止编程来帮助逃避细胞死亡 坏死。拟议的研究共同揭示了A20参与主动性和进步 AML，从而确定A20作为AML的治疗靶标的潜力。