Long non-coding RNAs in hematopoiesis and blood malignancy

造血和血液恶性肿瘤中的长非编码RNA

基本信息

批准号：
8875983
负责人：
Iannis Aifantis
金额：
$ 45.75万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-04 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8875983
关键词：
Acute Myelocytic Leukemia Acute T Cell Leukemia Acute leukemia Address Adult Affect Biological Biological Markers Blood Characteristics Child Chromatin Chromosome Mapping Code Cytokine Receptors DNA Data Data Set Diagnosis Disease Disease remission Drug Targeting Enhancers Family Flavoring Flow Cytometry Gene Expression Regulation Gene Targeting Genes Genetic Transcription Genome Growth Hematologic Neoplasms Hematopoiesis Human Human Cell Line Human Genome IGF1 gene IGF1R gene Individual Lead Malignant Neoplasms Maps Measurement Methodology Methods Modeling Molecular Molecular Conformation Mutation Myelogenous NOTCH1 gene Oncogenes Oncogenic Pharmaceutical Preparations Play Production Proteins RNA Interference Reader Regulator Genes Resolution Role Sampling Series Signal Transduction Stimulus Testing Time Transcript Transcriptional Activation Untranslated RNA Validation base cytokine data integration disease diagnosis evidence base global run on sequencing human disease in vivo inhibitor/antagonist leukemia novel public health relevance research study response small molecule targeted treatment therapeutic target tool transcription factor transcriptome sequencing tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Recent efforts to functionally annotate the human genome have revealed that up to 75% of our DNA is transcriptionally active. Since a very small portion of our genome encodes proteins many have hypothesized that a portion of this pervasive transcription results in production of long non-coding RNA. By generating high depth RNA-Seq datasets integrated with chromatin features, our lab and others have revealed the presence of many thousands of previously un-annotated lncRNAs, which are dynamically expressed in response to various stimuli in diverse cellular contexts. Despite these compelling advances, the vast majority of putative lncRNAs have not been proven to be functionally important, although a small portion have clearly been shown to play key regulatory roles. Most importantly, very little is known on the biological role of lncRNAs in human cancer. We provide here, using a combination of deep transcriptome sequencing, high-resolution transcription factor occupancy mapping and chromatin interaction data, the first comprehensive identification and characterization of lncRNA expression and function in T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematologic malignancy driven by oncogenic NOTCH1 transcriptional activity. Moreover, we provide the first map of oncogene (NOTCH1)-targeted lncRNAs in this tumor and identify an individual lncRNA (called LUNAR1) that appears to be essential for tumor growth as it controls cytokine (IGF1) signaling. These studies suggest that: a) lncRNAs could be used as both biomarkers and therapy targets in human cancer (see AIM1), b) more efficient methods for large-scale inference and validation of lncRNA function are needed to fully understand their biological significance (see AIM2) and, c) LUNAR1 is one of the first lncRNAs that can control growth of acute leukemia and a potential therapeutic target (see AIM3). In this application we address in detail all these important issues and attempt to directly connect lncRNA deregulation to leukemia initiation and progression.

描述（由适用提供）：最近注释人类基因组的最新努力表明，多达75％的DNA具有转录活性。由于我们的一小部分基因组编码蛋白质，许多人假设这种普遍转录的一部分导致长期非编码RNA的产生。通过生成与染色质特征集成的高深度RNA-seq数据集，我们的实验室和其他人揭示了数千个先前未经通知的LNCRNA的存在，这些LNCRNA是针对各种细胞环境的响应而动态表达的。尽管有这些令人信服的进步，但绝大多数推定的lncrnas尚未被证明在功能上很重要，尽管显然已经证明一小部分扮演着关键的监管角色。最重要的是，在人类癌症中LNCRNA的生物学作用知之甚少。我们在这里提供了深层转录组测序，高分辨率转录因子占用映射和染色质相互作用数据的结合，这是T细胞急性淋巴细胞白血病（T-ALL）中LNCRNA表达和功能的首次综合鉴定和表征，这是一种积极的血液学恶性疾病驱动。此外，我们在该肿瘤中提供了第一份癌细胞（Notch1）靶向的LNCRNA的地图，并鉴定单个lncRNA（称为lunar1），这似乎对于肿瘤的生长至关重要，因为它控制了细胞因子（IGF1）信号。 These studies suggest that: a) lncRNAs could be used as both biomarkers and therapy targets in human cancer (see AIM1), b) more efficient methods for large-scale inference and validation of lncRNA functions are needed to fully understand their biologicity (see AIM2) and, c) LUNAR1 is one of the first lncRNAs that can control growth of acute leukemia and a potential therapeutic target (see AIM3).在此应用程序中，我们详细介绍了所有这些重要问题，并试图将lncrna放松管制与白血病倡议和进步联系起来。