Remodeling of 3D chromatin in B cell acute leukemia and its impact on clinical outcome

B细胞急性白血病3D染色质重塑及其对临床结果的影响

• 批准号: 10631888
• 负责人: William L. Carroll
• 金额: $ 43.64万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631888
• 关键词: 3-Dimensional; Acute Lymphocytic Leukemia; Acute leukemia; Address; Adolescent; Affect; Architecture; Automobile Driving; B-Lymphocytes; Biology; Cancer Etiology; Cancer Patient; Cell Line; Cell Maintenance; Cells; Child; Childhood Leukemia; Chromatin; Chromatin Loop; Chromosomes; Clinical; Clonal Evolution; DNA; DNA Sequence Alteration; Data; Diagnosis; Disease; Disease Progression; Disease remission; Enhancers; Ensure; Epigenetic Process; Event; Evolution; Exhibits; Fishes; Gene Expression; Gene Expression Regulation; Genetic; Genome; Genomics; Growth; Hematologic Neoplasms; Heterogeneity; Imaging Techniques; In Vitro; Individual; Infant; Laboratories; Large-Scale Sequencing; Lesion; Maintenance; Malignant Neoplasms; Maps; Measures; Mediating; Methodology; Modeling; Modification; Molecular Conformation; Mutation; Neighborhoods; Outcome; Patients; Pharmacotherapy; Play; Population; Pre-Clinical Model; Process; Prognosis; RNA; Relapse; Resistance; Resolution; Role; Sampling; Structure; Subgroup; Techniques; Technology; Therapeutic; Variant; Work; acute leukemia cell; cellular imaging; childhood cancer mortality; chromosome conformation capture; clinical phenotype; cohort; computational pipelines; conventional therapy; effective therapy; epigenome; experience; experimental study; genetically modified cells; genome-wide; improved; in vitro Model; in vivo; in vivo Model; insight; leukemia; leukemic transformation; mortality; novel; patient derived xenograft model; precursor cell; promoter; relapse patients; response; side effect; single molecule; translational impact; treatment response; tumor; tumor progression; young adult

ABSTRACT While the outcomes for children with acute lymphoblastic leukemia (ALL) have improved dramatically over the past four decades, major challenges remain including the burden of conventional therapy and less progress in major subgroups making ALL one of the leading causes of cancer death in children. Thus, targeted, more effec- tive therapies are urgently needed. The current project builds on our recent studies implicating the epigenome in transformation and response to therapy. Recent advances in chromatin conformation capture techniques have revolutionized our understanding of chromatin organization and have provided novel insights at an unprece- dented level of detail. Several studies have identified biologically-relevant structures in DNA-DNA contact maps, such as A/B compartments, topologically-associating domains (TADs), and insulated neighborhoods, and have elucidated the role of chromatin architecture in gene regulation and maintenance of cell identity. A handful of very recent studies from our lab and others have shown that aberrant TAD activation or “rewiring” promoter- enhancer interactions can promote cancer growth. However, no study has yet addressed the disruptions of chro- matin organization on a genome-wide scale in cancer patients or how such disruptions modify the promoter- enhancer landscape leading to leukemia initiation and therapy resistance and relapse. This study aims to ad- dress these gaps by comparing the chromatin landscape in B ALL samples and normal B precursor cells to identify chromatin architecture associated with transformation and to chart the evolution of topographic changes from diagnosis to relapse using paired samples to discover 3D alterations associated with tumor progression. In preliminary data, we have analyzed a small pilot cohort of 12 patients with matched diagnosis/relapse samples. In this small cohort, we have already identified chromatin reorganization events at multiple levels: compartment switches, changes in intra-TAD chromatin interactions, establishment of enhancer-promoter loops and structural alterations that directly affect 3D topology. Such changes will be validated in preclinical models using genetically engineered cell lines in vitro and in vivo as well as patient derived xenografts (PDX). Finally, to examine the subclonal composition of promoter-enhancer loops we will use single cell DNA/RNA FISH and will use the same methodology to track evolution in PDX models.

抽象的 急性淋巴细胞白血病（全部）的儿童的结果在 在过去的四十年中，仍然存在重大挑战，包括燃烧常规疗法和更少的进展 主要亚组使儿童癌症死亡的所有主要原因之一。那是针对性的，更有效的 迫切需要疗法。当前的项目以我们最近的研究为基础，暗示了表观基因组 在转化和对治疗的反应中。染色质构象捕获技术的最新进展具有 彻底改变了我们对染色质组织的理解，并在一个无所事事的情况下提供了新的见解。 细节的水平。几项研究已经确定了在DNA-DNA接触图中与生物学相关的结构， 例如A/B隔室，拓扑结合的域（TADS）和绝缘社区，并具有 阐明了染色质结构在基因调节和维持细胞身份的作用。少数 我们实验室和其他人的最新研究表明，异常的TAD激活或“重新启动”启动子 - 增强子相互作用可以促进癌症的生长。但是，尚无研究解决CHRO的中断 MATIN组织在癌症患者的全基因组量表上，或这种干扰如何改变启动子 - 增强剂景观导致白血病倡议和耐药性和缓解性。这项研究旨在广告 通过比较B所有样品和正常B前体细胞中的染色质景观来打扮这些间隙 识别与转换相关的染色质体系结构并绘制地形变化的演变 从诊断到继电器，使用配对样品发现与肿瘤进展相关的3D改变。在 初步数据，我们分析了12例匹配诊断/复发样本的患者的小型驾驶员队列。 在这个小的队列中，我们已经确定了多个级别的染色质重组事件：车厢 开关，TAD内部染色质相互作用的变化，建立增强剂促销循环和结构 直接影响3D拓扑的变化。此类更改将在临床前模型中使用一般 体外和体内设计的细胞系以及患者衍生的Xenographictic（PDX）。最后，检查 启动子增强剂环的亚克隆组成我们将使用单细胞DNA/RNA鱼，并将使用相同 在PDX模型中跟踪进化的方法。