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.

项目摘要/摘要 从骨骼的造血干/祖细胞（HSPC）的扩张和进行性位移 在原发性骨髓纤维化（PMF）中观察到的骨髓到外周血表明ABELRANT通讯 干细胞与骨髓微环境（BMME）之间 这种疾病。 在大多数PMF病例中，几乎所有的肌loprolifeve都发现JAT CASCADE失调 但是，肿瘤（MPN）。 改变潜在的疾病并影响恶性造血干细胞，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的药理学干预的新目标 总体目的是确定与年龄启动有关的新信号传导机制 诱导的骨髓纤维化和相关MPN。 编码小鼠骨髓中的Abelson Interconor-1（ABI-1）衔接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显示ABI-1降低 蛋白质和转录水平，（3）ABI-1的丧失对SRC家族激酶（SFK）及其其活性产生积极影响 向STAT3和NFKB的下游信号传导，最后（4）恶性HSPC中的ABI-1丢失导致 粘附和静止的失调并诱导其化学抗性。 通过对SFK信号传导的积极影响及其与STAT3和NFKB的下游串扰的损失， 是在恶性干细胞水平上引发纤维化诱导变化的因素。 在以下三个特定目标中进行了测试。 骨髓特异性小鼠模型（ABI-1 BM KO）评估ABI-1损失对通信的影响 HSPC和BME及其在与年龄相关的骨髓纤维的发展中的作用。 我们将使用高级显微镜和生化阵列来阐明直接ABI-1的机制 使用ABI-1 BM KO在特定AIM 3中控制SFK和下游信号。 将评估SFK抑制对ABI-1-损伤诱导的骨髓纤维的影响。 阐明了通过恶性茎导致骨髓findusisd发展的ABI-1驱动机制 MPN中的细胞，并发现了直接解决其发病机理的潜在新治疗方法 战略利用新建立的动物模型，有可能使您提高您 了解肿瘤和基质细胞细胞相互作用。 从对癌细胞的关注转变为对癌症的更广泛，更复杂的理解 在微环境环境中存在的全身性疾病。