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.

摘要