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: 10387279
• 负责人: Jason Xu
• 金额: $ 5.18万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10387279
• 关键词: Accounting; Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute leukemia; Address; Automobile Driving; B-Lymphocytes; Biologic Characteristic; Biological; Biological Assay; Biological Models; Bone Marrow; CD32 Antigens; Cell Line; Cell surface; Cells; Cellular Assay; Characteristics; Childhood Leukemia; Chromatin; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Common Acute Lymphoblastic Leukemia; Computer Analysis; Coupled; Data; Data Analyses; Development; Diagnosis; Disease remission; Early treatment; Enrollment; Epigenetic Process; Equilibrium; Flow Cytometry; Gene Expression; Genes; Genetic; Genomics; Goals; Grant; Hematopoietic stem cells; Immunophenotyping; In complete remission; Inferior; Knowledge; Lead; Lymphoid; Lymphoid Cell; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Measurement; Modeling; Molecular; Morbidity - disease rate; Mutation; Myelogenous; Myeloid Cells; Outcome; Pathway interactions; Patients; Pharmacological Treatment; Phenotype; Plant Roots; Population; Postdoctoral Fellow; Process; Relapse; Residual Neoplasm; Sampling; Small Interfering RNA; Stains; Surface; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Transposase; Treatment Failure; United States National Institutes of Health; Work; base; cancer diagnosis; carcinogenesis; cell type; chemotherapy; cohort; conventional therapy; high risk; improved; mortality; multiple omics; myeloid cell development; novel; novel therapeutic intervention; progenitor; prognostic; prognostic signature; prospective; response; risk stratification; single-cell RNA sequencing; stem; stem-like cell; targeted treatment; therapy resistant; tool; transcriptome sequencing; transcriptomics; treatment response; validation studies

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.

项目摘要 急性淋巴细胞白血病（ALL）是最常见的儿科癌症，占新发癌症的近三分之一。 儿科癌症诊断。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，治疗失败率高， 持续存在于研究不足的ALL亚型，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2倍。 在诱导化疗结束时可能有可检测的残留疾病。我们假设这些引人注目的 对治疗反应的差异本质上植根于ETP-ALL的生物学特征， 使用高通量测量工具，如单细胞基因组学，可以进一步揭示。 COG的AALL 00344临床试验的完成，招募了325名ETP-ALL患者，代表了一个令人兴奋的结果。 有机会提高我们对ETP-ALL的理解，并确定治疗失败的生物学原因。在 目的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例ETP-ALL患者的转录组学特征和表观遗传特征。我们将寻求将ETP-ALL 在健康T细胞发育和其他儿科白血病的背景下的原始细胞。在目标2中，我们将比较ETP- 基于临床应答的ALL患者，并使用患者特异性异种移植模型功能性干扰基因 以及在无应答患者中富集的途径。我们的项目准备与批量测序数据协同 通过NIH X 01资助（HD 100702 -01）为325例ETP-ALL患者生成，特别是由于我们的 使用在单细胞数据中发现的亚克隆特异性标签对批量测序数据进行解卷积的能力。 我们相信这项工作有助于阐明ETP-ALL的遗传驱动因素，并确定靶点和细胞因子。 与治疗失败相关的人群，从而显著影响ETP的诊断和治疗， 所有.