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: 10524088
• 负责人: Patrycja Marta Dubielecka-Szczerba
• 金额: $ 1.09万
• 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/10524088
• 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; insight; mouse model; novel; novel therapeutic intervention; phosphoproteomics; polymerization; response; self-renewal; src-Family Kinases; stem; stem cells; therapeutic target; translational goal

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 欢迎的是，在大多数骨髓恶性肿瘤中，JAK/STAT信号传导不体 骨髓增生性肿瘤（MPN）中的JAK激活突变引发了抑制剂的发展 目标jak用于临床环境，而这些药物则没有改变 潜在疾病是因为DO不会退休的MPN直接MPN直接性恶性造血词干/祖细胞 （HSPC）。 MPN的发病机理。 需要有效治疗这些肿瘤并消除疾病的未知病原机制 启动MPN干细胞。 HSPC的维持，特别关注模块化调节HSPC的关键衔接蛋白 自我更新，区分和恶性转变。 一种此类衔接蛋白Abelson Intercontor-1（ABI-1）在定义HSPC表型的信号级联反应中。 我们最近的发现表明：（1）小鼠骨髓中ABI1基因的条件缺失诱导A 骨髓纤维化表型；（2）造血祖细胞和粒细胞 MPN-主要骨髓纤维化（PMF）显示ABI-1转录本和蛋白质水平降低，（3）ABI-1的丧失 积极影响SRC家族Kinacys（SFK）的活性以及向STAT3和NF-的下游信号传导 κB，导致HSPC自我更新和适应性的损害。 通过对HSPC自我更新和通过负调节的分化，一种重要且潜在的目标作用 SFK/STAT3/NF-κB炎症模块，其获得的缺失可以促进恶性肿瘤 对PMF的转换和计划将在以下三个特定的 目的。 确定ABI-1损失对HSPC信号传导和自我更新，差异和恶性的影响 转换。 标记技术在HSPC中定义ABI-1相互作用。 ABI-1缺陷HSPC和人类PMF茎/祖细胞的磷蛋白质组学分析 3我们将使用骨髓特异性ABI-1敲除小鼠模型来评估缺失的影响 HSPC的自我更新，分化和恶性转化的基质成分中的ABI-1。 支撑目的的压缩将提高我们对失调失调机制的理解 ABI-1/SFK/STAT3/NF-KB信号传导有助于HSPC的肿瘤诱导能力 知识将用于迈向我们的长期翻译，以识别治疗 靶向负责骨髓肿瘤起源的策略。