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

基本信息

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
项目类别：
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

项目摘要

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 在祖细胞致癌转化中作用的表征项目概要我们的总体目标是确定 ADAR1 在白血病前祖细胞致癌转化中的作用骨髓增殖性肿瘤（MPN）转化为自我更新的白血病干细胞（LSC）的最新研究。尽管如此，ADAR1 介导的 RNA 编辑是人类癌症进展的重要驱动因素。许多 RNA 编辑位点已被识别，ADAR1 介导的 RNA 编辑的功能相关性，特别是在初级患者样本中，这一问题仍未得到解决，这项研究代表了一个独特的机会。了解癌症干细胞中恶性 RNA 编辑驱动癌症进展的后果炎症细胞因子驱动的 ADAR1 激活与治疗耐药有关。将祖细胞恶性重编程为多种自我更新的癌症干细胞此前，我们发现 ADAR1 可以增强白血病前期祖细胞的自我更新。慢性粒细胞白血病 (CML)，部分是由于 A-to-I 编辑诱导的 GSK3β 错误剪接造成的， ADAR1 可以防止自我更新激动剂 β-连环蛋白的降解。最近，ADAR1 已被证明发挥着重要作用。 ADAR1 在 microRNA 生物发生中发挥重要作用，并特别损害 let-7 家族 microRNA 的产生。在从骨髓纤维化（MF）发展为继发性急性髓系白血病（sAML）的过程中，该蛋白也上调。在这笔资助中，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、生存能力、 MPN 慢病毒转导后原代患者祖细胞和正常祖细胞中的细胞周期和细胞周期鉴于 >90% 的 A 到 I 编辑事件发生在灵长类特异性 Alu 元素的背景下，将使用人和小鼠评估 Alu 序列对 ADAR1 功能的必要性其次，RNA编辑对let-7 microRNA生物发生和降解的影响。最后，我们发现 ADAR1 编辑 APOBEC3 胞苷脱氨酶，从而引入 C 到 T。此外，多个 A 到 I 编辑位点发生在内含子、外显子中。以及 APOBEC3D 和 3G 的蛋白质编码区，表明 ADAR1 可能调节 APOBEC 因此，我们的目标是破译 ADAR1 在 APOBEC3 失调中的作用。以及在白血病前祖细胞进化为白血病过程中引入DNA超突变模式除了极大地扩展我们对祖细胞中 A-to-I 编辑功能的了解之外。维护，该研究计划将为恶性 ADAR1 编辑酶检测和开发提供信息抑制策略可能有助于防止 MPN 进展为急性髓系白血病。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

A-to-I RNA editing in leukemia stem cells - set ADAR1 on the radar.

白血病干细胞中的 A 到 I RNA 编辑 - 在雷达上设置 ADAR1。

DOI：
10.18632/oncotarget.27261
发表时间：
2019
期刊：
Oncotarget
影响因子：
0
作者：
Jiang,Qingfei;Diep,Raymond;Jamieson,Catriona
通讯作者：
Jamieson,Catriona

Malignant A-to-I RNA editing by ADAR1 drives T-cell acute lymphoblastic leukemia relapse via attenuating dsRNA sensing.

ADAR1 的恶性 A-to-I RNA 编辑通过减弱 dsRNA 传感驱动 T 细胞急性淋巴细胞白血病复发。

DOI：
10.21203/rs.3.rs-2444524/v2
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Rivera,Maria;Zhang,Haoran;Pham,Jessica;Isquith,Jane;Zhou,QingchenJenny;Sasik,Roman;Mark,Adam;Ma,Wenxue;Holm,Frida;Fisch,KathleenM;Kuo,DennisJohn;Jamieson,Catriona;Jiang,Qingfei
通讯作者：
Jiang,Qingfei