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：
10573148
负责人：
Jason Xu
金额：
$ 5.27万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
https://reporter.nih.gov/project-details/10573148
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 Cytoplasm Data Data Analyses Development Diagnosis Disease remission Early identification 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 Membrane Proteins Modeling Molecular Morbidity - disease rate Mutation Myelogenous Myeloid Cells Outcome Pathway interactions Patients Pharmacological Treatment Phenotype Population Postdoctoral Fellow Process Publishing Regimen Relapse Residual Neoplasm Sampling Small Interfering RNA Stains T-Cell Development T-Lymphocyte Testing Therapeutic Thymus Gland Transposase Treatment Failure United States National Institutes of Health Work 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 cells stem-like cell synergism targeted treatment therapy resistant tool transcriptome sequencing transcriptomics treatment response validation studies

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 Cytoplasm Data Data Analyses Development Diagnosis Disease remission Early identification 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 Membrane Proteins Modeling Molecular Morbidity - disease rate Mutation Myelogenous Myeloid Cells Outcome Pathway interactions Patients Pharmacological Treatment Phenotype Population Postdoctoral Fellow Process Publishing Regimen Relapse Residual Neoplasm Sampling Small Interfering RNA Stains T-Cell Development T-Lymphocyte Testing Therapeutic Thymus Gland Transposase Treatment Failure United States National Institutes of Health Work 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 cells stem-like cell synergism targeted treatment therapy resistant tool transcriptome sequencing transcriptomics treatment response validation studies

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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.

项目摘要急性淋巴细胞白血病（ALL）是最常见的小儿癌，占新的近1个小儿癌诊断。尽管与普通的所有亚型相关的死亡率和发病率都有由于化学疗法和风险分层的进步，治疗失败率高，大大改善了坚持所有的亚型，例如早期的T细胞前体急性淋巴细胞白血病（ETP-ALL）。 ETP-ALL患者在化学疗法的第一个月失败的7倍，非ETP所有患者的发生率是所有患者的率，并且是两倍的在诱导化疗结束时可能患有可检测的残留疾病。我们假设这些罢工对治疗反应的差异本质上根植于ETP的生物学特征，这可以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，该试验招收了325例ETP ALL患者，代表了令人兴奋的有机会提高我们对ETP的理解，并确定治疗衰竭的生物学原因。在 AIM 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患者的转录组特征和表观遗传学特征和表观遗传学特征。我们将寻求放置ETP-all 在健康的T细胞发育和其他儿科白血病的背景下进行爆炸。在AIM 2中，我们将比较ETP- 所有基于临床反应的患者，并使用患者特异性的武器模型在功能上扰动基因和富含无反应患者的途径。我们的项目中毒以与批量测序数据协同作用通过NIH X01赠款（HD100702-01）为325例ETP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异性标志来反应散装测序数据。我们认为拟议的工作可以帮助阐明ETP的遗传驱动因素，并识别目标和细胞与治疗失败相关的人群，因此显着影响ETP的诊断和治疗全部。