The role of Abelson interactor 1 (Abi-1) in hematopoietic stem cell self-renewal and malignant transformation

Abelson相互作用子1（Abi-1）在造血干细胞自我更新和恶性转化中的作用

• 批准号: 9982974
• 负责人: Patrycja Marta Dubielecka-Szczerba
• 金额: $ 36.83万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-24 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982974
• 关键词: Actins; Adaptor Signaling Protein; Affect; Attention; Blood; Bone Marrow; Cell Proliferation Regulation; Cells; Clinical; Communication; Complement; Critical Pathways; Data; Development; Disease; Embryo; Event; Genes; Goals; Heart Abnormalities; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Human; Impairment; Inflammation; Inflammatory; JAK2 gene; Knockout Mice; Knowledge; Label; MAP Kinase Gene; Maintenance; Malignant - descriptor; Mediating; Modeling; Mus; Mutation; Myeloproliferative disease; NF-kappa B; Neoplasms; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Phosphotransferases; Placenta; Play; Primary Myelofibrosis; Process; Proteins; Proteomics; Regulation; Research; Role; STAT3 gene; Signal Pathway; Signal Transduction; Technology; Testing; Therapeutic; Transcript; base; cancer stem cell; curative treatments; disease natural history; fitness; granulocyte; hematopoietic stem cell self-renewal; inhibitor/antagonist; insight; mouse model; novel; novel therapeutic intervention; phosphoproteomics; polymerization; response; self-renewal; src-Family Kinases; stem; stem cells; therapeutic target

PROJECT SUMMARY/ABSTRACT It is well established that JAK/STAT signaling is dysregulated in most myeloid malignancies. Identification of JAK-activating mutations in myeloproliferative neoplasms (MPNs) prompted the development of inhibitors that target JAK for use in the clinical setting. While these agents provide a symptomatic response, they do not alter the underlying disease in that they do not target MPN-initiating malignant hematopoietic stem/progenitor cells (HSPCs). This observation has been interpreted as indicating that alternative signaling pathways contribute to the pathogenesis of MPNs. The present proposal is based on the premise that identification of hitherto unknown pathogenic mechanisms will be required to effectively treat these neoplasms and eradicate disease initiating MPN stem cells. Our long-term goal is to define signal transduction events responsible for systemic maintenance of HSPCs, with particular focus on key adapter proteins that modulate signals regulating HSPCs self-renewal, differentiation and their malignant transformation. Our direct objective is to elucidate the role of one such adapter protein, Abelson interactor-1 (Abi-1), in signaling cascades that define the HSPC phenotype. Our recent findings indicate that: (1) conditional deletion of the Abi1 gene in mouse bone marrow induces a myelofibrotic phenotype; (2) hematopoietic progenitors and granulocytes from patients with the most severe of MPNs - primary myelofibrosis (PMF) show decreased Abi-1 transcript and protein levels, and; (3) loss of Abi-1 positively affects the activity of Src Family Kinases (SFKs) and their downstream signaling to STAT3 and NF- κB, resulting in impairment of HSPC self-renewal and fitness. Our central hypothesis is that Abi-1 plays an important and potentially targetable role in HSPC self-renewal and differentiation via negative regulation of the SFK/STAT3/NF-κB inflammatory module, and that its acquired absence can promote malignant transformation and progression to PMF. Our central hypothesis will be tested in the following three Specific Aims. In Specific Aim 1 we will use our new hematopoietic cell-specific Abi-1 knockout mouse model to determine the effect of Abi-1 loss on HSPC signaling and self-renewal, differentiation and malignant transformation. In Specific Aim 2, we will use advanced proteomics combined with proximity-dependent labelling technology to define the Abi-1 interactome in HSPCs. This approach will be complemented by phosphoproteomic analyses of Abi-1-deficient HSPCs and human PMF stem/progenitor cells. In Specific Aim 3 we will use our bone marrow stroma-specific Abi-1 knockout mouse model to assess the effect of deletion of Abi-1 in the stromal component on the self-renewal, differentiation and malignant transformation of HSPCs. Completion of the proposed aims will advance our understanding of the mechanisms by which dysregulation of Abi-1/SFK/STAT3/NF-kB signaling contributes to the neoplasm-inducing capacities of HSPCs. This new knowledge will be used to make progress toward our long-term translational goal of identifying therapeutic strategies that target cells responsible for the origin of myeloproliferative neoplasms.

项目摘要/摘要 众所周知，JAK/STAT信号在大多数髓系恶性肿瘤中调节失调。身份识别 骨髓增生性肿瘤(MPN)中的JAK激活突变促使抑制物的开发 靶向JAK用于临床环境。虽然这些药物提供了症状反应，但它们不会改变 潜在的疾病，因为它们不针对MPN启动的恶性造血干/祖细胞 (HSPC)。这一观察结果被解释为表明，替代信号通路有助于 MPNS的发病机制。目前的提议是基于这样一个前提，即迄今确定 有效治疗这些肿瘤和根除疾病需要未知的致病机制。 启动MPN干细胞。我们的长期目标是定义负责系统性疾病的信号转导事件 HSPC的维护，特别关注调节HSPC信号的关键适配蛋白 自我更新、分化及其恶变。我们的直接目标是阐明 一种这样的适配蛋白，Abelson Interact-1(Abi-1)，在定义HSPC表型的信号级联中。 我们最近的发现表明：(1)小鼠骨髓中ABI1基因的条件性缺失诱导了 骨髓纤维化表型；(2)最严重急性髓系白血病患者的造血祖细胞和粒细胞 MPNS-原发骨髓纤维化(PMF)表现为Abi-1转录和蛋白水平降低，以及；(3)Abi-1丢失 正向影响Src家族激酶(SFK)的活性及其下游信号转导STAT3和NF-2 κB，导致HSPC自我更新和体能受损。我们的中心假设是Abi-1在 通过负调控在HSPC自我更新和分化中的重要和潜在的靶向性作用 SFK/STAT3/NF-κB炎症模块及其获得性缺失可促进恶性进展 向PMF转型和进步。我们的中心假设将在以下三个具体情况下得到检验 目标。在特定的目标1中，我们将使用我们的新的造血细胞特异性Abi-1基因敲除小鼠模型来 确定Abi-1缺失对HSPC信号转导及自我更新、分化和恶性的影响 转型。在特定目标2中，我们将使用高级蛋白质组学和邻近依赖 用于确定HSPC中Abi-1相互作用组的标记技术。这一方法将得到以下补充 Abi-1缺陷的HSPC和人PMF干/祖细胞的磷酸蛋白质组学分析。以特定的目标 3我们将使用我们的骨髓基质特异性Abi-1基因敲除小鼠模型来评估缺失 基质成分ABI-1对HSPC自我更新、分化及恶变的影响 完成拟议的目标将促进我们对监管失调的机制的理解 ABI-1/SFK/STAT3/NF-kB信号通路参与HSPC的致瘤作用。这是一项新的 知识将被用来朝着我们的长期翻译目标取得进展，即确定治疗方法 针对负责骨髓增生性肿瘤起源的细胞的策略。