Investigating the role of epitranscriptomic A-to-I RNA editing in T-cell acute lymphoblastic leukemia

研究表观转录组 A-to-I RNA 编辑在 T 细胞急性淋巴细胞白血病中的作用

基本信息

批准号：
10220900
负责人：
Qingfei Jiang
金额：
$ 19.12万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220900
关键词：
14 year old Ablation Acute Lymphocytic Leukemia Acute T Cell Leukemia Address Adenosine Adult Adult Precursor T Lymphoblastic Leukemia Age Apoptosis B-Cell Development Basic Science Biological Assay Biology Bone Marrow CD34 gene Cancer Patient Cell Maintenance Cell Survival Cell physiology Cells Characteristics Childhood Clinical Data Deaminase Detection Development Development Plans Diagnostic Disease Disease Progression Drug resistance Engraftment Event Future Gene Expression Gene Expression Profile Generations Genes Goals Grant Hematologic Neoplasms Human IL7 gene Immunocompromised Host Impairment Inflammation Inflammatory Inosine Investigation JAK2 gene Janus kinase Maintenance Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Malignant lymphoid neoplasm Mediating Medical Messenger RNA MicroRNAs Modeling Mus Mutation NOTCH1 gene Notch Signaling Pathway Oncogenic Pathway interactions Patients Peripheral Pharmacology Phenotype Population RNA RNA Editing RNA I Regulatory Pathway Relapse Research Research Ethics Resistance Risk Role Sampling Signal Pathway Signal Transduction Specimen System T-Lymphocyte Testing Therapeutic Training Transcript Translational Research Umbilical Cord Blood Validation Xenograft Model Xenograft procedure adenosine deaminase base biobank cancer stem cell cancer type career development cell transformation chemotherapy cytokine data management epitranscriptomics gamma secretase human model in vivo inhibitor/antagonist knock-down leadership development leukemia initiating cell mouse model mutant new therapeutic target notch protein novel novel therapeutics overexpression premalignant prevent progenitor self-renewal small hairpin RNA stem cell genes stem cells therapeutic target therapy development therapy resistant tool transcriptome transcriptome sequencing

项目摘要

Project Summary The ultimate goal of this proposal is to address a compelling unmet medical need to identify novel epitranscriptomic mechanisms of oncogenic transformation that will guide development of diagnostic and therapeutic strategies capable of predicting and preventing progression of T-cell acute lymphoblastic leukemia (T-ALL). Acute lymphoblastic leukemia (ALL) is the most prevalent hematological cancer in children younger than 14 years of age. Despite progress in intensive chemotherapy, 20-25% of pediatric and over 50% of adult patients show resistance to therapy and relapse. Widespread aberrant epitranscriptomic ADAR1-mediated adenosine-to-inosine (A-to-I) RNA editing has been associated with clinical characteristics of several cancer types and generation of leukemia initiating cells (LICs) with enhanced pro-survival and self-renewal capacity. Interestingly, activation of janus kinase (JAK)/STAT signaling by interleukin-7 (IL-7) drives expression of key stem cell regulatory pathway ADAR1-LIN28 and pro-survival factors in hematological malignancies including T-ALL. Our central hypothesis is that mutational pro-inflammatory signals, such as NOTCH and JAK/STAT signaling pathway, induce aberrant RNA editing driven by ADAR1 activation in T-ALL-initiating cells that accentuated by enhanced survival and self-renewal capacity. The three specific aims will be (1) examine if the ADAR1-mediated RNA editing promotes oncogenic transformation of normal T cell progenitor to T-ALL LICs by enhancing T-ALL LIC survival and self-renewal pathways; (2); examine whether ADAR1 activity is enhanced in T-ALL LIC cells due to NOTCH or JAK/STAT signaling pathway activation, and lastly (3) determine whether direct inhibition of ADAR1 activity by shRNA strategy impairs the survival and self-renewal impairs T-ALL LIC maintenance. This proposal will utilize established biorepository of primary T-ALL patient specimen, along with age-matched healthy control samples. In addition, lentiviral-based tools and established robust in vivo human xenograft T-ALL mouse models will be used for selective ablation of ADAR1 transcripts to thoroughly investigate the relationship between ADAR1 expression and generation of drug-resistant T- ALL-initiating LIC cells. Detailed functional and mechanistic lentiviral-directed transcript overexpression and knockdown studies will validate sensitive whole transcriptome RNA-Sequencing that correlate ADAR1 expression with LIC survival and self-renewal signaling pathway and stem cell gene expression signatures. This research strategy is uniquely integrated into my career development plan, including additional trainings in data management, basic and translational research, research ethics, and professional and leadership development. By providing a more mechanistic understanding of the role of ADAR1 in cancer, this grant will inform future RNA editase detection and inhibition strategies that may help to obviate cancer resistance and relapse.

项目概要该提案的最终目标是解决迫切的未满足的医疗需求，以识别新的致癌转化的表观转录组机制将指导诊断和治疗的发展能够预测和预防 T 细胞急性淋巴细胞白血病进展的治疗策略白血病（T-ALL）。急性淋巴细胞白血病（ALL）是世界上最常见的血液癌症 14 岁以下的儿童。尽管强化化疗取得了进展，但仍有 20-25% 的儿童超过50%的成年患者表现出对治疗的抵抗力和复发。普遍存在异常现象表观转录组 ADAR1 介导的腺苷至肌苷 (A-to-I) RNA 编辑与几种癌症类型的临床特征和白血病起始细胞（LIC）的产生增强生存和自我更新能力。有趣的是，Janus 激酶 (JAK)/STAT 的激活白细胞介素 7 (IL-7) 信号传导驱动关键干细胞调节通路 ADAR1-LIN28 的表达，包括 T-ALL 在内的血液系统恶性肿瘤中的促生存因素。我们的中心假设是突变的促炎信号，例如 NOTCH 和 JAK/STAT 信号通路，会诱发异常 T-ALL 起始细胞中 ADAR1 激活驱动 RNA 编辑，并通过提高存活率来增强和自我更新能力。三个具体目标是 (1) 检查 ADAR1 介导的 RNA 编辑是否通过增强 T-ALL LIC 促进正常 T 细胞祖细胞向 T-ALL LIC 的致癌转化生存和自我更新的途径； (2);检查 T-ALL LIC 细胞中 ADAR1 活性是否增强由于NOTCH或JAK/STAT信号通路激活，最后（3）确定是否直接 shRNA 策略抑制 ADAR1 活性会损害 T-ALL LIC 的生存和自我更新维护。该提案将利用已建立的原发性 T-ALL 患者标本生物储存库，以及年龄匹配的健康对照样本。此外，基于慢病毒的工具和已建立的稳健的体内人类异种移植 T-ALL 小鼠模型将用于选择性消融 ADAR1 转录本深入研究 ADAR1 表达与耐药 T-产生之间的关系 ALL 启动 LIC 细胞。慢病毒定向转录物过表达的详细功能和机制和敲低研究将验证相关的敏感全转录组 RNA 测序 ADAR1 表达与 LIC 存活和自我更新信号通路以及干细胞基因表达签名。这项研究策略独特地融入了我的职业发展计划，包括数据管理、基础研究和转化研究、研究伦理等方面的额外培训专业和领导力发展。通过提供对作用的更机械的理解 ADAR1 在癌症中的作用，这项资助将为未来的 RNA 编辑酶检测和抑制策略提供信息，这些策略可能有助于消除癌症耐药性和复发。