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

基本信息

批准号：
10381569
负责人：
William L. Carroll
金额：
$ 44.26万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/10381569
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 Custom DNA DNA Sequence Alteration Data Diagnosis Disease Disease Progression Disease remission Enhancers Ensure Epigenetic Process Event Evolution Exhibits Gene Expression Gene Expression Regulation 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 Neighborhoods Outcome Patients Pharmacotherapy Play Population Pre-Clinical Model Process Prognosis RNA Relapse Resistance Resolution Role Sampling Structure Subgroup Techniques Technology Therapeutic Variant Work base 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

项目摘要

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.

抽象的虽然急性淋巴细胞白血病 (ALL) 儿童的治疗结果比过去有了显着改善过去四十年，重大挑战依然存在，包括传统治疗的负担和治疗进展缓慢主要亚组使 ALL 成为儿童癌症死亡的主要原因之一，因此，有针对性、更有效。当前的项目建立在我们最近涉及表观基因组的研究的基础上。染色质构象捕获技术的最新进展。彻底改变了我们对染色质组织的理解，并以前所未有的方式提供了新颖的见解一些研究已经确定了 DNA-DNA 接触图中的生物学相关结构，例如 A/B 隔室、拓扑关联域 (TAD) 和绝缘邻域，并且具有阐明了染色质结构在基因调控和细胞身份维持中的作用。我们实验室和其他实验室的最新研究表明，异常的 TAD 激活或“重新布线”启动子增强子相互作用可以促进癌症生长。然而，尚未有研究解决染色体的破坏问题。癌症患者在全基因组范围内的 matin 组织或这种破坏如何改变启动子 - 增强子景观导致白血病发生、治疗耐药和复发。通过比较 B ALL 样本和正常 B 前体细胞中的染色质景观来弥补这些差距识别与转化相关的染色质结构并绘制地形变化的演变图使用配对样本从诊断到复发，发现与肿瘤进展相关的 3D 改变。初步数据，我们分析了 12 名具有匹配诊断/复发样本的患者的小型试点队列。在这个小队列中，我们已经在多个层面上识别了染色质重组事件：开关、TAD 内染色质相互作用的变化、增强子-启动子环的建立和结构直接影响 3D 拓扑的改变将在临床前模型中使用遗传进行验证。最后，研究体外和体内工程细胞系以及患者来源的异种移植物（PDX）。启动子-增强子环的亚克隆组成我们将使用单细胞 DNA/RNA FISH 并将使用相同的跟踪 PDX 模型演变的方法。