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:
- 金额:$ 44.26万
- 依托单位:
- 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:
- 关键词:3-DimensionalAcute Lymphocytic LeukemiaAcute leukemiaAddressAdolescentAffectArchitectureAutomobile DrivingB-LymphocytesBiologyCancer EtiologyCancer PatientCell LineCell MaintenanceCellsChildChildhood LeukemiaChromatinChromatin LoopChromosomesClinicalClonal EvolutionCustomDNADNA Sequence AlterationDataDiagnosisDiseaseDisease ProgressionDisease remissionEnhancersEnsureEpigenetic ProcessEventEvolutionExhibitsGene ExpressionGene Expression RegulationGenomeGenomicsGrowthHematologic NeoplasmsHeterogeneityImaging TechniquesIn VitroIndividualInfantLaboratoriesLarge-Scale SequencingLesionMaintenanceMalignant NeoplasmsMapsMeasuresMediatingMethodologyModelingModificationMolecular ConformationNeighborhoodsOutcomePatientsPharmacotherapyPlayPopulationPre-Clinical ModelProcessPrognosisRNARelapseResistanceResolutionRoleSamplingStructureSubgroupTechniquesTechnologyTherapeuticVariantWorkbasecellular imagingchildhood cancer mortalitychromosome conformation captureclinical phenotypecohortcomputational pipelinesconventional therapyeffective therapyepigenomeexperienceexperimental studygenetically modified cellsgenome-wideimprovedin vitro Modelin vivoin vivo Modelinsightleukemialeukemic transformationmortalitynovelpatient derived xenograft modelprecursor cellpromoterrelapse patientsresponseside effectsingle moleculetranslational impacttreatment responsetumortumor progressionyoung 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.
摘要
虽然儿童急性淋巴细胞白血病(ALL)的预后在2008年有了显著改善,
在过去的四十年里,主要的挑战仍然存在,包括传统治疗的负担和
主要的亚群使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,
迫切需要积极的治疗方法。目前的项目建立在我们最近的研究基础上,
转化和对治疗的反应。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,并提供了新的见解,
细节的层次有所降低。几项研究已经在DNA-DNA接触图中确定了生物学相关的结构,
例如A/B区、拓扑关联域(TADs)和绝缘邻域,并且具有
阐明了染色质结构在基因调控和维持细胞特性中的作用。少数
我们实验室和其他人最近的研究表明,异常的启动子激活或“重新连接”启动子-
增强子相互作用可以促进癌症生长。然而,目前还没有研究表明,
在癌症患者的全基因组范围内的组织或这种破坏如何修改启动子-
增强子景观导致白血病启动、治疗耐药性和复发。本研究旨在-
通过比较B ALL样本和正常B前体细胞的染色质景观,
识别与转化相关的染色质结构,并绘制地形变化的演变图
从诊断到复发,使用配对样本发现与肿瘤进展相关的3D变化。在
根据初步数据,我们分析了12名患者的小型试点队列,这些患者具有匹配的诊断/复发样本。
在这个小队列中,我们已经在多个水平上鉴定了染色质重组事件:
开关,胞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拓扑的更改。这些变化将在临床前模型中进行验证,
体外和体内工程化细胞系以及患者来源的异种移植物(PDX)。最后,为了检查
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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William L. Carroll其他文献
Outstanding outcomes with two low intensity regimens in children with low-risk B-ALL: a report from COG AALL0932
低危 B-ALL 儿童采用两种低强度方案的显著结果:来自 COG AALL0932 的报告
- DOI:
10.1038/s41375-023-01870-8 - 发表时间:
2023-03-25 - 期刊:
- 影响因子:13.400
- 作者:
Reuven J. Schore;Anne L. Angiolillo;John A. Kairalla;Meenakshi Devidas;Karen R. Rabin;Patrick Zweidler-McKay;Michael J. Borowitz;Brent Wood;Andrew J. Carroll;Nyla A. Heerema;Mary V. Relling;Johann Hitzler;Nina S. Kadan-Lottick;Kelly Maloney;Cindy Wang;William L. Carroll;Naomi J. Winick;Elizabeth A. Raetz;Mignon L. Loh;Stephen P. Hunger - 通讯作者:
Stephen P. Hunger
emSubtype Dependent Drug Resistance Alterations in Relapsed Childhood B-ALL: A Children's Oncology Group Study/em
- DOI:
10.1182/blood-2022-166489 - 发表时间:
2022-11-15 - 期刊:
- 影响因子:23.100
- 作者:
Xiaotu Ma;Lingyun Ji;Yanling Liu;Ying Shao;Heather Mulder;Pandurang Kolekar;Quang Tran;Jinghui Zhang;John Easton;William L. Carroll;Patrick A. Brown;Mignon L. Loh - 通讯作者:
Mignon L. Loh
A emD e Novo/em Supernumerary Ring Chromosome 1 Causes B-Cell Acute Lymphoblastic Leukemia in Monozygotic Twins Due to Independent and Partially Convergent Evolutionary Trajectories
一个全新的超数环状染色体 1 由于独立且部分趋同的进化轨迹导致同卵双胞胎患 B 细胞急性淋巴细胞白血病
- DOI:
10.1182/blood-2023-181194 - 发表时间:
2023-11-02 - 期刊:
- 影响因子:23.100
- 作者:
Jesús Gutiérrez-Abril;Gunes Gundem;Elise Fiala;Konstantinos Liosis;Noushin Farnoud;Daniel Leongamornlert;Anu Amallraja;Juan E. Arango Ossa;Dylan Domenico;Max F. Levine;Juan Santiago Medina Martinez;Michael F. Walsh;Sylwia Jasinski;Andrew L. Kung;Neerav N. Shukla;William L. Carroll;Elli Papaemmanuil - 通讯作者:
Elli Papaemmanuil
The Role of over-Expressed β emGlobin/em in Driving Relapsed B - Cell Acute Lymphoblastic Leukemia (B-ALL)
过表达的β珠蛋白在驱动复发性 B 细胞急性淋巴细胞白血病(B-ALL)中的作用
- DOI:
10.1182/blood-2023-180976 - 发表时间:
2023-11-02 - 期刊:
- 影响因子:23.100
- 作者:
Jessica Krugman;Sylwia Jasinski;Elizabeth A. Raetz;Nikki Evensen;William L. Carroll - 通讯作者:
William L. Carroll
The Role of over-Expressed β <em>Globin</em> in Driving Relapsed B - Cell Acute Lymphoblastic Leukemia (B-ALL)
- DOI:
10.1182/blood-2023-180976 - 发表时间:
2023-11-02 - 期刊:
- 影响因子:
- 作者:
Jessica Krugman;Sylwia Jasinski;Elizabeth A. Raetz;Nikki Evensen;William L. Carroll - 通讯作者:
William L. Carroll
William L. Carroll的其他文献
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{{ truncateString('William L. Carroll', 18)}}的其他基金
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:
10184002 - 财政年份:2021
- 资助金额:
$ 44.26万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 44.26万 - 项目类别:
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