Functional dissection of oncogenic enhancers

致癌增强子的功能剖析

基本信息

批准号：
9111911
负责人：
Daniel Herranz
金额：
$ 17.09万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2015-07-16 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9111911
关键词：
Accounting Acute Lymphocytic Leukemia Acute T Cell Leukemia Address Adult T-ALL Automobile Driving Binding Biology CRISPR/Cas technology Cell Lineage Child Childhood Chromatin Clinical Clinical Trials Code Complex DNA Development Disease Disease Progression Dissection Effectiveness Enhancers Gene Expression Genes Genetic Genomics Goals Hematologic Neoplasms Human Knockout Mice Lesion Light Malignant Neoplasms Malignant neoplasm of lung Maps Mediating Mentors Molecular Mutant Strains Mice Mutation NOTCH1 gene Non-Small-Cell Lung Carcinoma Oncogenes Oncogenic Outcome Pathogenesis Patients Pattern Phase Play Proteins Recurrence Recurrent Malignant Neoplasm Refractory Regulation Regulatory Element Relapse Research Proposals Resistance Role Signal Transduction Site Solid Neoplasm T-Cell Development T-Cell Immunologic Specificity T-Cell Leukemia T-Lymphocyte Testing Tissues Transcriptional Regulation Untranslated RNA antileukemic agent base chemotherapy chromatin immunoprecipitation chromatin modification chromatin protein enhancer binding protein gamma secretase genome editing in vivo inhibitor/antagonist insight leukemia leukemia treatment novel novel strategies outcome forecast programs public health relevance repaired targeted cancer therapy targeted treatment therapeutic target tool transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): Functional dissection of oncogenic enhancers T cell acute lymphoblastic leukemia (T-ALL) accounts for 10% to 15% of pediatric and 25% of adult T-ALL cases and was originally identified as highly aggressive tumor associated to poor prognosis. Despite recent progress in the treatment of this disease, the prognosis of patients with relapsed and refractory T-ALL remain extremely poor, underscoring the need to identify molecular mechanisms responsible for disease progression and to develop more effective antileukemic drugs. We recently identified N-Me, a NOTCH1-bound enhancer driving MYC expression in T-cells. This enhancer is recurrently amplified in T-ALL and is strictly required for NOTCH1-induced transformation. These results demonstrate a critical role for long-range regulatory sequences in the pathogenesis of NOTCH1-induced T-ALL and highlight the potential for enhancer-driven gene expression mechanisms as a therapeutic target for the treatment of human cancer. Based on our results, we hypothesize that N-Me regulates gene expression in T- ALL by interacting with additional as yet uncharacterized long-range regulatory sequences and via the activity of T-cell lineage specific transcription factors. Moreover, we propose that oncogenic NOTCH1 controls additional key long range enhancers controlling master regulators of the leukemia oncogenic program in addition to MYC and that long range regulatory enhancers play a critical role in the pathogenesis solid tumors. The goal of this proposal is to advance our understanding of the basic mechanisms of long-range transcriptional regulation in human cancer as a first step to ultimately provide new tools and targets for the treatment of this disease. Toward this objective we propose: (i) To analyze the mechanisms of N-Me mediated Myc expression in T-ALL (Aim 1); (ii) To functionally dissect the role of N-Me in the control of Myc expression in vivo using CRISPR/Cas9 genome editing tools (Aim 2); and (iii) To identify NOTCH1-bound enhancers in solid tumors (Aim 3).

描述（由适用提供）：致癌增强剂T细胞急性淋巴细胞白血病（T-ALL）的功能截断占小儿的10％至15％，而成年T-ALL病例的25％，最初被鉴定为与不良预后相关的高度攻击性肿瘤。尽管该疾病的治疗最近进展，但复发和难治性T-All的患者的预后仍然极为差，强调了鉴定导致疾病进展的分子机制并开发出更有效的抗尿液药物的需求。我们最近确定了N-ME，这是一种结合T-Cell中MYC表达的Notch1结合的增强子。该增强器在T-All中反复放大，严格要求 Notch1诱导的转换。这些结果表明，远程调节序列在Notch1诱导的T-all的发病机理中起着至关重要的作用，并突出了增强子驱动基因表达机制的潜力，作为治疗人类癌症的治疗靶标。基于我们的结果，我们假设N-ME通过与其他尚未尚未表征的长期调节序列以及T细胞谱系特定转录因子的活性来调节T-全部T-全部调节基因表达。此外，我们建议致癌Notch1控制着其他关键的远距离增强剂，这些远距离增强剂除MYC外，还控制着白血病致癌计划的主调节剂，并且远程调节增强剂在发病机理实体瘤中起着至关重要的作用。该提案的目的是促进我们对人类癌症远程转录调节的基本机制的理解，这是最终为治疗这种疾病提供新工具和目标的第一步。为了实现这一目标，我们提出：（i）分析N-ME介导的MYC表达在T-ALL中的机制（AIM 1）；（ii）使用CRISPR/CAS9基因组编辑工具在功能上剖析N-ME在体内控制MYC表达中的作用（AIM 2）；（iii）确定实体瘤中Notch1结合的增强子（AIM 3）。