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.

项目摘要该提案的最终目标是解决识别新颖的令人信服的未满足医疗需求肿瘤转化的表面转录机制，将指导诊断和能够预测和预防T细胞急性淋巴细胞的治疗策略白血病（T-All）。急性淋巴细胞白血病（ALL）是最普遍的血液学癌症 14岁以下的儿童。尽管进展进行了强化化学疗法，但小儿20-25％超过50％的成年患者表现出对治疗和复发的抵抗力。广泛的异常同意ADAR1介导的腺苷对肌苷（A-TO-I）RNA编辑与几种癌症类型的临床特征和白血病引发细胞（LIC）的临床特征增强的亲生和自我更新能力。有趣的是，激活Janus激酶（JAK）/Stat 白介素7（IL-7）的信号传导驱动了关键干细胞调节途径ADAR1-LIN28和血液学恶性肿瘤中的促生物因素，包括T-ALL。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，引起异常由ADAR1激活驱动的RNA编辑在T-All Initating细胞中，这些细胞通过增强的生存增强和自我更新能力。这三个特定目标将是（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的致癌转化生存和自我更新途径；（2）;检查T-ALL LIC细胞中ADAR1活性是否增强由于缺口或jak/stat信号通路激活，最后（3）确定是否直接通过SHRNA策略抑制ADAR1活性会损害生存和自我更新会损害T-ALL LIC 维护。该建议将利用既定的原发性T-ALL患者标本的生物座席，以及年龄匹配的健康对照样品。此外，基于慢病毒的工具并建立了强大的工具体内人异种移植T-ALL小鼠模型将用于选择性消融ADAR1转录本彻底研究ADAR1表达与耐药T-的产生之间的关系通知的LIC细胞。详细的功能和机械慢病毒指导的转录本过表达敲低的研究将验证敏感的整个转录组RNA-RNA - 将其关联具有LIC生存和自我更新信号通路和干细胞基因表达的ADAR1表达签名。该研究策略唯一地整合到我的职业发展计划中，包括有关数据管理，基础和转化研究，研究伦理和的其他培训专业和领导力发展。通过对对角色的作用有更机械的理解癌症中的ADAR1，该赠款将为未来的RNA编辑酶检测和抑制策略提供信息有助于消除癌症的抗性和复发。