Unrestricted A20 activity in acute myeloid leukemia

急性髓系白血病中 A20 活性不受限制

基本信息

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
项目类别：
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

项目摘要

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靶蛋白的泛素链对于细胞内信号转导至关重要。编辑活动负责免疫反应和程序性坏死的负调节限制 NF-kB 信号传导和 RIP 信号传导分别与 A20 的失活突变相关。然而，有些出乎意料的是，我们确定获得性 A20 功能可能会发生。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，可能会导致死亡。虽然这种情况可以发生在任何年龄，但最常见于那些年龄段。 60岁以上，随着人口预期寿命的延长，患病率预计会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个体来说，遗传和表观遗传事件的复杂相互作用也是如此。尽管人们对 AML 的机制有了更好的了解，但仍有助于 AML 的发病机制。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 升高此外，白血病小鼠中 A20 的缺失与 AML 患者的总生存期较短有关。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 缺失对健康小鼠骨髓的影响是微不足道的。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。分别通过电子显微镜观察，并通过坏死抑制剂治疗挽救了细胞死亡。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，而 A20 已经有很好的进展。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。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了 AML 的发病机制。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。总之，拟议的研究旨在揭示 A20 参与坏死的发生和进展。 AML，从而确定 A20 作为 AML 治疗靶点的潜力。