Deciphering Inflammation in Myeloproliferative Neoplasia Progression

解读骨髓增生性肿瘤进展中的炎症

基本信息

批准号：
9911171
负责人：
MICHELLE SEMPKOWSKI CROW
金额：
$ 6.53万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-30 至 2021-03-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9911171
关键词：
Acute Myelocytic Leukemia Animal Model Apoptosis Bar Codes Bone Marrow Cell Compartmentation Cells Chronic Clonal Evolution Clonal Expansion Coculture Techniques Collection Color DNA DNA Damage DNA Repair DNA Sequence Alteration Data Defect Development Disease Disease Progression Evolution Exposure to Flow Cytometry Frequencies Genetic Genomic Instability Goals Hematopoiesis Hematopoietic Hematopoietic stem cells In Vitro Inflammation Inflammatory Interruption Knockout Mice Lead Lentivirus Vector Link Malignant Neoplasms Measures Modeling Molecular Mus Mutagenesis Mutation Myelofibrosis Myelogenous Myeloid Cells Myeloproliferative disease NF-kappa B Neoplasms Nitric Oxide Osteitis Oxygen Patients Pharmacology Phenotype Population Process Production Reactive Nitrogen Species Reporter Reporting Research Design Risk Role Sampling Series Signal Transduction Solid System Testing Therapeutic Intervention Time Transplantation Treatment Efficacy Up-Regulation Work bcr-abl Fusion Proteins cancer initiation chemokine cytokine de novo mutation design disorder prevention falls genomic data genotoxicity homologous recombination image reconstruction in vitro Model in vivo intravital imaging leukemia leukemic transformation mathematical model mutant next generation sequencing notch protein novel therapeutic intervention oxidation predictive tools prevent progenitor repaired replication stress stress reactivity tool transplant model treatment strategy tumor progression

项目摘要

Project Summary/Abstract Background: Myeloproliferative Neoplasms (MPNs) are hematopoietic stem cell disorders in which myeloid progenitors expand excessively while retaining a normal ability to differentiate, leading to abnormal accumulation of mature myeloid cells. Currently, there are approximately 300,000 patients living with BCR/ABL-negative MPN, a heterogeneous class of the disease characterized by chronic evolution, unsatisfactory treatment strategies, and unpredictable progression to Acute Myeloid Leukemia (AML). While the genetic landscape of MPN patients over time is complicated, the one common denominator of all MPNs is chronic inflammation. Objective/Hypothesis: Our preliminary studies indicate that inflammation leads to DNA damage and genomic instability, contributing to the development of myeloproliferative disorder. We therefore propose to elucidate the molecular mechanisms. We hypothesize that chronic inflammation in the bone marrow (BM) niche: i) promotes proliferation and genomic instability in hematopoietic cells; and ii) cooperates with underlying genetic mutations to promote clonal expansion and selection, as well as the acquisition of de novo mutations, accelerating disease progression and transformation to AML. Specific Aims: (1) To determine whether an inflamed BM niche leads to clonal selection and disease progression in JAK2V617F-driven MPN; (2) To investigate the direct impact of an inflamed BM microenvironment on DNA damage and mutagenesis in JAK2V617F-driven MPN; and (3) To evaluate the impact of miR-155 suppression in MPN and disease progression. Study Design: We have developed an animal model where loss of RBPJ/Notch signaling in the BM microenvironment leads to chronic inflammation. We will utilize this model to study the role of inflammation on JAK2V617F-driven MPN. MPN cells will be exposed to an RBPJKO inflamed BM microenvironment using both in vivo transplantation and in vitro co-culture. We will investigate whether inflammation promotes clonal selection and disease progression in JAK2V617F-driven MPN using a colored barcode lentiviral tracking system. We will also explore whether inflammation directly causes DNA damage and mutagenesis over the course of JAK2V617F- driven MPN progression. Mathematical modeling will be employed to integrate this information with genomic data, to develop predictive tools for disease progression and to identify a temporal window of therapeutic intervention. Finally, we will examine the potential therapeutic efficacy of pharmacologic miR-155 blockade in preventing MPN disease progression and/or transformation. Cancer Relevance: This work will contribute to our understanding of the mechanisms of MPN disease progression and how inflammation cooperates with underlying genetic mutations such as JAK2V617F to drive disease. Ultimately, this will provide us with tools to better identify patients at risk for MPN progression and provide new therapeutic approaches for the prevention of disease progression and transformation to AML.

项目概要/摘要背景：骨髓增生性肿瘤（MPN）是一种造血干细胞疾病，其中骨髓细胞祖细胞过度扩增，同时保留正常分化能力，导致异常积累成熟的骨髓细胞。目前，大约有 300,000 名 BCR/ABL 阴性 MPN 患者，一种异质性疾病，其特征是慢性演变、治疗策略不令人满意，以及不可预测的急性髓系白血病 (AML) 进展。 MPN 患者的遗传状况随着时间的推移，情况变得很复杂，所有 MPN 的一个共同点是慢性炎症。目的/假设：我们的初步研究表明炎症会导致 DNA 损伤和基因组损伤不稳定，导致骨髓增生性疾病的发展。因此，我们建议阐明分子机制。我们假设骨髓 (BM) 生态位中的慢性炎症：i) 促进造血细胞的增殖和基因组不稳定性； ii) 与潜在的基因突变合作促进克隆扩增和选择，以及获得从头突变，加速疾病的发生 AML 的进展和转化。具体目标：(1) 确定发炎的 BM 生态位是否会导致克隆选择和疾病 JAK2V617F 驱动的 MPN 进展； (2) 研究发炎的骨髓微环境的直接影响 JAK2V617F 驱动的 MPN 中 DNA 损伤和突变的研究； (3) 评估 miR-155 的影响抑制 MPN 和疾病进展。研究设计：我们开发了一种动物模型，其中 BM 中 RBPJ/Notch 信号丢失微环境导致慢性炎症。我们将利用这个模型来研究炎症对 JAK2V617F驱动的MPN。 MPN 细胞将暴露于 RBPJKO 发炎的 BM 微环境中，同时使用体内移植和体外共培养。我们将研究炎症是否促进克隆选择使用彩色条形码慢病毒追踪系统来评估 JAK2V617F 驱动的 MPN 的疾病进展。我们将还探讨了 JAK2V617F 过程中炎症是否直接导致 DNA 损伤和突变驱动 MPN 进展。将采用数学模型将这些信息与基因组整合起来数据，开发疾病进展的预测工具并确定治疗的时间窗口干涉。最后，我们将检查药物 miR-155 阻断的潜在治疗效果预防 MPN 疾病进展和/或转化。癌症相关性：这项工作将有助于我们了解 MPN 疾病的机制进展以及炎症如何与 JAK2V617F 等潜在基因突变配合来驱动疾病。最终，这将为我们提供工具来更好地识别有 MPN 进展风险的患者，并为预防疾病进展和转化为 AML 提供新的治疗方法。