Interrogating the Role of Abelson Interactor 1 in Age-Related Myelofibrosis

探讨 Abelson Interactor 1 在年龄相关性骨髓纤维化中的作用

• 批准号: 9356957
• 负责人: Patrycja Marta Dubielecka-Szczerba
• 金额: $ 22.87万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9356957
• 关键词: Acute Myelocytic Leukemia; Adaptor Signaling Protein; Address; Adhesions; Adhesiveness; Affect; Age; Animal Model; Automobile Driving; Binding Sites; Biochemical; Biological Assay; Blood Vessels; Bone Marrow; CD34 gene; Cell Adhesion Molecules; Cell Aging; Cell Communication; Cell Cycle; Chronic Myeloid Leukemia; Clinical; Communication; Complex; Dasatinib; Data; Development; Disease; Effectiveness; Environment; Etiology; Fibrosis; Fluorescence Resonance Energy Transfer; Gene Deletion; Gene Expression; Goals; Hematopoietic stem cells; In Vitro; Ineffective Hematopoiesis; Inflammatory; Integrin alpha4; Intervention; Knowledge; Lead; Maintenance; Malignant - descriptor; Malignant Neoplasms; Maps; Marrow; Microscopy; Modeling; Molecular; Mus; Myelofibrosis; Myeloproliferative disease; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pharmacology; Phenotype; Primary Myelofibrosis; Process; Proteins; Role; STAT3 gene; Signal Pathway; Signal Transduction; Stem cells; Stromal Cells; Systemic disease; Testing; Transcript; Treatment Efficacy; Tyrosine Kinase Inhibitor; adhesion receptor; age related; base; cancer cell; cancer stem cell; chemokine; cytokine; granulocyte; inhibitor/antagonist; malignant phenotype; mouse model; mutant; neoplastic cell; novel therapeutic intervention; outcome forecast; peripheral blood; predictive marker; src-Family Kinases; therapy resistant

PROJECT SUMMARY/ABSTRACT Expansion and progressive displacement of hematopoietic stem/progenitor cells (HSPCs) from the bone marrow to peripheral blood observed in primary myelofibrosis (PMF) suggests that aberrant communication between stem cells and the bone marrow microenvironment (BMME) is key to understanding the etiology of this disease. Molecular mechanisms that contribute to PMF pathology at the stem cell level are not known. JAK/STAT cascade was found to be dysregulated in most PMF cases and in nearly all myeloproliferative neoplasms (MPNs). However, the extent to which currently available inhibitors that target JAK/STAT pathway alter the underlying disease and affect malignant hematopoietic stem cells is not clear. Our long term goal is to better understand the molecular processes that control abnormal interactions between malignant HSPCs and their BMME, and identify new targets for pharmacological intervention in PMF and other MPNs. The overall objective of this application is to identify new signaling mechanisms involved in the initiation of age- induced myelofibrosis and related MPNs. Our recent findings indicate that (1) conditional deletion of the gene encoding the Abelson interactor-1 (Abi-1) adapter protein in mouse bone marrow induces myelofibrotic phenotype, (2) hematopoietic progenitors and granulocytes from patients with PMF show decreased Abi-1 protein and transcript levels, (3) loss of Abi-1 positively affects activity of Src Family Kinases (SFKs) and their downstream signaling to STAT3 and NFkB, and finally (4) loss of Abi-1 in malignant HSPCs leads to dysregulation of adhesion and quiescence and induces their chemoresistance. Our central hypothesis is that loss of Abi-1, through a positive effect on SFKs signaling and its downstream cross-talk with STAT3 and NFkB, is a factor that initiates fibrosis-inducing changes at the malignant stem cell level. Our central hypothesis will be tested in the following three Specific Aims. In Specific Aim 1 we will use our established Abi-1 conditional bone marrow-specific mouse model (Abi-1 BM KO) to assess the effect of Abi-1 loss on the communication between HSPCs and BMME and its role in the development of age-related myelofibrosis. In Specific Aim 2, we will use advanced microscopy and biochemical arrays to elucidate the mechanism by which Abi-1 directly controls SFKs and their downstream signaling to STAT3 and NFκB. In Specific Aim 3 using Abi-1 BM KO we will evaluate the effects of SFKs inhibition on Abi-1-loss-induced myelofibrosis. Completion of these aims will elucidate Abi-1-driven mechanisms that lead to the development of marrow fibrosis induced by malignant stem cells in MPNs, and uncover potential new therapeutic approaches that directly address their pathogenesis. Our strategy utilizes newly established animal models and has the potential to significantly advance the understanding of tumor and stromal cell interactions. This knowledge will contribute to an emerging conceptual shift in the field from a focus on cancer cells to a broader and more complex understanding of cancer as a systemic disease existing in a microenvironmental context.

项目摘要/摘要 骨造血干/祖细胞的扩增和渐进性移位 在原发性骨髓纤维化(PMF)中观察到的骨髓与外周血之间的异常通讯 干细胞与骨髓微环境(BMME)之间的关系是理解骨质疏松症病因的关键 这种病。在干细胞水平上导致PMF病理的分子机制尚不清楚。 在大多数PMF病例和几乎所有的骨髓增生性疾病中，JAK/STAT级联信号转导系统被发现是失调的 肿瘤(MPN)。然而，目前可用的针对JAK/STAT通路的抑制剂的程度 改变基础疾病和影响恶性造血干细胞尚不清楚。我们的长期目标是 为了更好地了解控制恶性HSPC之间异常相互作用的分子过程 并确定PMF和其他MPN的药物干预的新靶点。这个 本申请的总体目标是确定参与启动AGE的新的信号机制。 诱导的骨髓纤维化及相关的MPN。我们最近的发现表明：(1)有条件地删除该基因 在小鼠骨髓中编码Abi-1接头蛋白诱导骨髓纤维化 表型，(2)PMF患者的造血祖细胞和粒细胞Abi-1减少 蛋白和转录水平，(3)Abi-1的缺失正向影响Src家族激酶(SFK)及其受体的活性。 下游信号转导到STAT3和NFkB，最后(4)恶性HSPC中Abi-1的缺失导致 黏附和静止的调节失调，并诱导它们产生化疗耐药。我们的中心假设是 Abi-1的丢失，通过对SFKs信号及其与STAT3和NFkB的下游串扰的积极影响， 是一种在恶性干细胞水平上启动纤维化诱导变化的因素。我们的中心假设是 在以下三个具体目标中进行了测试。在具体目标1中，我们将使用我们确立的Abi-1条件 骨髓特异性小鼠模型(Abi-1 BM KO)评价Abi-1缺失对通讯功能的影响 HSPC和BMME之间的关系及其在老年性骨髓纤维化发展中的作用。在具体目标2中， 我们将使用先进的显微镜和生化阵列来阐明Abi-1直接 控制SFK及其对STAT3和NFκB的下游信号。在特定目标3中使用Abi-1 BM KO WE 将评估抑制SFKs对Abi-1丢失诱导的骨髓纤维化的影响。完成这些目标将 阐明Abi-1在恶性干细胞诱导骨髓纤维化中的作用机制 在MPN中的细胞，并发现潜在的新的治疗方法，直接解决其发病机制。我们的 该策略利用了新建立的动物模型，并有可能显著推进 了解肿瘤和间质细胞的相互作用。这一知识将有助于形成一个新的概念 该领域从对癌细胞的关注转向对癌症的更广泛和更复杂的理解 存在于微环境中的系统性疾病。