Analysis of Developmental Arrest and Treatment Resistance in High-risk T-ALL
高危 T-ALL 发育停滞和治疗抵抗分析
基本信息
- 批准号:10387279
- 负责人:
- 金额:$ 5.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-21 至 2025-01-20
- 项目状态:未结题
- 来源:
- 关键词:AccountingAcute Lymphocytic LeukemiaAcute Myelocytic LeukemiaAcute leukemiaAddressAutomobile DrivingB-LymphocytesBiologic CharacteristicBiologicalBiological AssayBiological ModelsBone MarrowCD32 AntigensCell LineCell surfaceCellsCellular AssayCharacteristicsChildhood LeukemiaChromatinClinicalClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCommon Acute Lymphoblastic LeukemiaComputer AnalysisCoupledDataData AnalysesDevelopmentDiagnosisDisease remissionEarly treatmentEnrollmentEpigenetic ProcessEquilibriumFlow CytometryGene ExpressionGenesGeneticGenomicsGoalsGrantHematopoietic stem cellsImmunophenotypingIn complete remissionInferiorKnowledgeLeadLymphoidLymphoid CellMalignant Childhood NeoplasmMalignant NeoplasmsMapsMeasurementModelingMolecularMorbidity - disease rateMutationMyelogenousMyeloid CellsOutcomePathway interactionsPatientsPharmacological TreatmentPhenotypePlant RootsPopulationPostdoctoral FellowProcessRelapseResidual NeoplasmSamplingSmall Interfering RNAStainsSurfaceT-Cell DevelopmentT-LymphocyteTestingTherapeuticThymus GlandTransposaseTreatment FailureUnited States National Institutes of HealthWorkbasecancer diagnosiscarcinogenesiscell typechemotherapycohortconventional therapyhigh riskimprovedmortalitymultiple omicsmyeloid cell developmentnovelnovel therapeutic interventionprogenitorprognosticprognostic signatureprospectiveresponserisk stratificationsingle-cell RNA sequencingstemstem-like celltargeted treatmenttherapy resistanttooltranscriptome sequencingtranscriptomicstreatment responsevalidation studies
项目摘要
Project Summary
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, accounting for nearly 1 in 3 new
pediatric cancer diagnoses. Though mortality and morbidity associated with common ALL subtypes have
drastically improved as a result of advances in chemotherapy and risk stratification, high rates of treatment failure
persist in understudied subtypes of ALL, such as early T-cell precursor acute lymphoblastic leukemia (ETP-ALL).
ETP-ALL patients fail the first month of chemotherapy at 7.7x the rate of non-ETP ALL patients and are twice as
likely to have detectable residual disease at end of induction chemotherapy. We hypothesize that these striking
differences in response to treatment are intrinsically rooted in biological characteristics of ETP-ALL, which can
be further revealed using high-throughput measurement tools, such as single-cell genomics.
The completion of COG’s AALL00344 clinical trial, which enrolled 325 ETP-ALL patients, represents an exciting
opportunity to improve our understanding of ETP-ALL and identify the biological reasons for treatment failure. In
Aim 1, we will use single cell transcriptomics and single cell chromatin accessibility to investigate clonal diversity,
transcriptomic features and epigenetic signatures in 30 patients with ETP-ALL. We will seek to place ETP-ALL
blasts in context of healthy T-cell development and other pediatric leukemias. In Aim 2, we will compare ETP-
ALL patients based on clinical response and use patient-specific xenograph models to functionally perturb genes
and pathways enriched in non-responding patients. Our project is poised to synergize with bulk sequencing data
being generated for 325 ETP-ALL patients through an NIH X01 grant (HD100702-01), specifically due to our
ability to deconvolute bulk sequencing data using subclone-specific signatures discovered in single cell data.
We believe the proposed work can help to elucidate the genetic drivers of ETP-ALL and identify targets and cell
populations associated with treatment failure, thus significantly impacting the diagnosis and treatment of ETP-
ALL.
项目概要
急性淋巴细胞白血病 (ALL) 是最常见的儿科癌症,占新发儿童癌症的近三分之一
小儿癌症诊断。尽管与常见 ALL 亚型相关的死亡率和发病率
由于化疗和风险分层的进步,治疗失败率大幅提高
持续存在于尚未研究的 ALL 亚型中,例如早期 T 细胞前体急性淋巴细胞白血病 (ETP-ALL)。
ETP-ALL 患者第一个月化疗失败率是非 ETP ALL 患者的 7.7 倍,是非 ETP ALL 患者的两倍
在诱导化疗结束时可能有可检测到的残留疾病。我们假设这些引人注目的
对治疗反应的差异本质上源于 ETP-ALL 的生物学特征,这可以
使用高通量测量工具(例如单细胞基因组学)进一步揭示。
COG 的 AALL00344 临床试验的完成,招募了 325 名 ETP-ALL 患者,这是一项令人兴奋的成果
提高我们对 ETP-ALL 的理解并确定治疗失败的生物学原因的机会。在
目标 1,我们将使用单细胞转录组学和单细胞染色质可及性来研究克隆多样性,
30 名 ETP-ALL 患者的转录组特征和表观遗传特征。我们将寻求放置 ETP-ALL
健康 T 细胞发育和其他儿童白血病背景下的原始细胞。在目标 2 中,我们将比较 ETP-
所有患者均基于临床反应并使用患者特异性异种模型来干扰基因功能
以及无反应患者中丰富的途径。我们的项目准备与批量测序数据产生协同作用
通过 NIH X01 拨款 (HD100702-01) 为 325 名 ETP-ALL 患者生成,特别是由于我们
能够使用单细胞数据中发现的亚克隆特异性特征对批量测序数据进行解卷积。
我们相信拟议的工作可以帮助阐明 ETP-ALL 的遗传驱动因素并确定靶标和细胞
与治疗失败相关的人群,从而显着影响 ETP 的诊断和治疗
全部。
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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{{ truncateString('Jason Xu', 18)}}的其他基金
Analysis of Developmental Arrest and Treatment Resistance in High-risk T-ALL
高危 T-ALL 发育停滞和治疗抵抗分析
- 批准号:
10573148 - 财政年份:2022
- 资助金额:
$ 5.18万 - 项目类别:
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