Characterization of the Role of ADAR1 in Oncogenic Transformation of Progenitors

ADAR1 在祖细胞致癌转化中作用的表征

• 批准号: 10056196
• 负责人: Catriona Helen Macleod Jamieson
• 金额: $ 35.46万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-08 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10056196
• 关键词: ABL1 gene; Acute Myelocytic Leukemia; Acute leukemia; Address; Adenosine; Agonist; Alu Elements; Biogenesis; Blast Phase; Cancer Etiology; Cell Compartmentation; Cell Cycle; Cell Maintenance; Cells; Characteristics; Chronic Myeloid Leukemia; Chronic-Phase Myeloid Leukemia; Clinical; Coculture Techniques; Cytidine Deaminase; DNA; DNA Sequence Alteration; Data; Deaminase; Detection; Development; Diagnostic; Event; Evolution; Family; Family member; Generations; Goals; Grant; Hematopoietic stem cells; Human; Impairment; Inflammatory; Inosine; JAK2 gene; Knowledge; Malignant - descriptor; Malignant Neoplasms; Mediating; MicroRNAs; Modeling; Modification; Morbidity - disease rate; Mus; Mutagenesis; Mutation; Myelofibrosis; Myeloproliferative disease; Oncogenes; Oncogenic; Open Reading Frames; Patients; Pattern; Play; Primates; Production; RNA; RNA Editing; RNA I; Research; Role; Sampling; Secondary to; Site; Therapeutic; Transcript; adenosine deaminase; apolipoprotein B mRNA editing enzyme; bcr-abl Fusion Proteins; beta catenin; cancer stem cell; cytokine; leukemic stem cell; leukemic transformation; mortality; mouse model; mutant; polypeptide; premalignant; prevent; progenitor; programs; protein function; self-renewal; stem cell differentiation; stem cells; therapy resistant; tumor progression; ABL1 gene; Acute Myelocytic Leukemia; Acute leukemia; Address; Adenosine; Agonist; Alu Elements; Biogenesis; Blast Phase; Cancer Etiology; Cell Compartmentation; Cell Cycle; Cell Maintenance; Cells; Characteristics; Chronic Myeloid Leukemia; Chronic-Phase Myeloid Leukemia; Clinical; Coculture Techniques; Cytidine Deaminase; DNA; DNA Sequence Alteration; Data; Deaminase; Detection; Development; Diagnostic; Event; Evolution; Family; Family member; Generations; Goals; Grant; Hematopoietic stem cells; Human; Impairment; Inflammatory; Inosine; JAK2 gene; Knowledge; Malignant - descriptor; Malignant Neoplasms; Mediating; MicroRNAs; Modeling; Modification; Morbidity - disease rate; Mus; Mutagenesis; Mutation; Myelofibrosis; Myeloproliferative disease; Oncogenes; Oncogenic; Open Reading Frames; Patients; Pattern; Play; Primates; Production; RNA; RNA Editing; RNA I; Research; Role; Sampling; Secondary to; Site; Therapeutic; Transcript; adenosine deaminase; apolipoprotein B mRNA editing enzyme; bcr-abl Fusion Proteins; beta catenin; cancer stem cell; cytokine; leukemic stem cell; leukemic transformation; mortality; mouse model; mutant; polypeptide; premalignant; prevent; progenitor; programs; protein function; self-renewal; stem cell differentiation; stem cells; therapy resistant; tumor progression

Title: Characterization of the Role of ADAR1 in Oncogenic Transformation of Progenitors Project Summary Our overall goal is to define the role of ADAR1 in the oncogenic transformation of pre-leukemic progenitors in myeloproliferative neoplasms (MPNs) into self-renewing leukemia stem cells (LSCs). Recent research suggests that ADAR1-mediated RNA editing is an essential driver of human cancer progression. Though many RNA editing sites have been identified, the functional relevance of ADAR1-mediated RNA editing, especially in primary patient samples, is still unresolved. This study represents a unique opportunity to understand the consequences of malignant RNA editing in cancer stem cells that drive cancer progression and therapeutic resistance. Inflammatory cytokine driven activation of ADAR1 has been implicated in malignant reprogramming of progenitors into self-renewing cancer stem cells in a broad array of malignancies. Previously, we showed that ADAR1 enhances self-renewal of pre-leukemic progenitors in chronic myeloid leukemia (CML), in part as a result of A-to-I editing induced missplicing of GSK3β, which prevents degradation of the self-renewal agonist, β-catenin. More recently, ADAR1 has been shown to play a role in microRNA biogenesis and specifically impairs let-7 family microRNA production. Notably, ADAR1 is also upregulated during progression from myelofibrosis (MF) to secondary acute myeloid leukemia (sAML). In this grant, we will first examine if ADAR1-mediated RNA editing can alter self-renewal capacity, survival, and cell cycle in primary patient progenitors and normal progenitors following lentiviral transduction with MPN oncogenes. Given that >90% of A-to-I editing events occur in the context of primate-specific Alu elements, the necessity of Alu sequences for ADAR1 function will be assessed using both human and mouse progenitors. Secondly, the impact of RNA editing on let-7 microRNA biogenesis and degradation will be determined. Lastly, we discovered that ADAR1 edits APOBEC3 cytidine deaminase, which introduces C-to-T mutations in a broad array of malignancies. Moreover, multiple A-to-I editing sites occur in intronic, exonic, as well as protein coding regions of APOBEC3D and 3G, suggesting that ADAR1 might regulate APOBEC expression and protein function. Thus, we aim to decipher the role of ADAR1 in deregulation of APOBEC3s and introduction of DNA hypermutation patterns during evolution of pre-leukemic progenitors into leukemia stem cells. In addition to vastly expanding our knowledge of A-to-I editing function in progenitor cell maintenance, this research program will inform the development of malignant ADAR1 editase detection and inhibition strategies that may help to prevent progression of MPNs to acute myeloid leukemia.

标题：adar1在祖细胞的致癌转化中的作用的表征 项目摘要 我们的总体目标是定义AD​​AR1在白细胞前祖细胞中的致癌转化中的作用 骨髓增生性肿瘤（MPN）为自我更新白血病干细胞（LSC）。最近的研究 表明ADAR1介导的RNA编辑是人类癌症进展的重要驱动力。尽管 已经确定了许多RNA编辑位点，即ADAR1介导的RNA编辑的功能相关性， 特别是在原发性患者样本中，仍未解决。这项研究代表了一个独特的机会 了解促进癌症进展的癌症干细胞中恶性RNA编辑的后果 和热电阻。 ADAR1的炎症细胞因子驱动激活已与 在一系列广泛的阵列中，祖细胞对祖细胞的恶性重编程 恶性肿瘤。以前，我们表明ADAR1增强了在 慢性髓样白血病（CML），部分是由于A-to-i编辑引起的GSK3β的失误而导致的。 防止自我更新激动剂β-catenin的降解。最近，ADAR1已显示出 在microRNA生物发生中的作用，特别会损害Let-7家族microRNA的产生。值得注意的是，Adar1是 从骨髓纤维化（MF）到继发性急性髓样白血病（SAML）的过程中也上调。 在这笔赠款中，我们将首先检查ADAR1介导的RNA编辑是否可以改变自我更新能力，生存， 用MPN慢病毒转导后，初级患者祖细胞和正常祖细胞中的细胞周期和细胞周期 癌基因。鉴于> 90％的A到I编辑事件发生在私人特定的ALU元素的背景下， ALU序列的ADAR1函数的必要序列将使用人和小鼠评估 祖先。其次，RNA编辑对Let-7 MicroRNA生物发生和降解的影响将是 决定。最后，我们发现ADAR1编辑Apobec3 cytidine deaminase，该酶引入了C-TO-T 一系列恶性肿瘤中的突变。此外，多个A到I编辑站点出现在内含子的外显子中，如 以及APOBEC3D和3G的蛋白质编码区域，表明ADAR1可能调节APOBEC 表达和蛋白质功能。这，我们的目的是破译ADAR1在放松管​​制中的作用 并引入白细胞前祖细胞演变为白血病期间的DNA超数模式 干细胞。除了大大扩展我们对祖细胞中A到I编辑功能的了解 维护，该研究计划将为恶性ADAR1编辑酶检测和 可能有助于防止MPN急性髓样白血病的抑制策略。