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: 10210269
• 负责人: Patrycja Marta Dubielecka-Szczerba
• 金额: $ 21.77万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10210269
• 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 Communication; Cell Cycle; Chemoresistance; Chronic Myeloid Leukemia; Clinical; Communication; Complex; Dasatinib; Data; Development; Disease; 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; Prognosis; Proteins; Role; STAT3 gene; Signal Pathway; Signal Transduction; Stromal Cells; Systemic disease; Testing; Transcript; Tyrosine Kinase Inhibitor; adhesion receptor; age related; base; cancer cell; cancer stem cell; chemokine; cytokine; effectiveness evaluation; granulocyte; inhibitor/antagonist; malignant phenotype; mouse model; mutant; neoplastic cell; novel therapeutic intervention; peripheral blood; predictive marker; src-Family Kinases; stem cell aging; stem cells; therapeutically effective; 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.

项目概要/摘要 造血干细胞/祖细胞 (HSPC) 从骨中扩增并逐渐移位 在原发性骨髓纤维化 (PMF) 中观察到的骨髓到外周血表明异常的通讯 干细胞和骨髓微环境（BMME）之间的关系是理解骨髓微环境病因的关键 这种病。在干细胞水平上导致 PMF 病理学的分子机制尚不清楚。 发现 JAK/STAT 级联在大多数 PMF 病例和几乎所有骨髓增殖性病例中失调 肿瘤（MPN）。然而，目前可用的针对 JAK/STAT 通路的抑制剂的程度 改变基础疾病并影响恶性造血干细胞尚不清楚。我们的长期目标是 更好地了解控制恶性 HSPC 之间异常相互作用的分子过程 及其 BMME，并确定 PMF 和其他 MPN 药物干预的新目标。这 该应用的总体目标是确定参与年龄启动的新信号传导机制。 诱导的骨髓纤维化和相关的 MPN。我们最近的研究结果表明（1）基因的条件删除 小鼠骨髓中编码 Abelson 相互作用蛋白 1 (Abi-1) 接头蛋白可诱导骨髓纤维化 表型，(2) PMF 患者的造血祖细胞和粒细胞显示 Abi-1 减少 蛋白质和转录水平，(3) Abi-1 的缺失对 Src 家族激酶 (SFK) 及其活性产生积极影响 STAT3 和 NFkB 的下游信号传导，最后 (4) 恶性 HSPC 中 Abi-1 的丢失导致 粘附和静止的失调并诱导其化学耐药性。我们的中心假设是 通过对 SFK 信号传导及其下游与 STAT3 和 NFkB 的串扰产生积极影响，Abi-1 丢失， 是在恶性干细胞水平上引发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，我们将使用我们已建立的 Abi-1 条件 骨髓特异性小鼠模型 (Abi-1 BM KO)，用于评估 Abi-1 缺失对沟通的影响 HSPC 和 BMME 之间的关系及其在年龄相关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 直接作用的机制 控制 SFK 及其下游至 STAT3 和 NFκB 的信号传导。在使用 Abi-1 BM KO 的特定目标 3 中，我们 将评估 SFK 抑制对 Abi-1 丢失诱导的骨髓纤维化的影响。完成这些目标将 阐明导致恶性干细胞诱导的骨髓纤维化发展的 Abi-1 驱动机制 细胞，并发现直接解决其发病机制的潜在新治疗方法。我们的 该策略利用新建立的动物模型，有可能显着推进 了解肿瘤和基质细胞的相互作用。这些知识将有助于形成一个新兴的概念 该领域从关注癌细胞转向更广泛、更复杂地理解癌症作为一种疾病 存在于微环境背景下的全身性疾病。