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Enhancer Dysregulation in AML

AML 中的增强子失调

基本信息

批准号：
10582664
负责人：
Yali Dou
金额：
$ 54.86万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
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：
2019-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10582664
关键词：
Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Acute leukemia Binding Biological Markers CDX2 gene Cells Chromatin Clinical DNA Data Diagnosis Disease Distal Embryo Enhancers Epigenetic Process Event Future Gene Expression Profile Gene Expression Regulation Genes Genetic Transcription Global Change HOXA9 gene Hematopoietic Histones Homeobox Human In Vitro Literature Lymphoblastic Leukemia MEIS1 gene MLL gene Malignant - descriptor Malignant Neoplasms Mediating Medical Methyltransferase Mission Mixed-Lineage Leukemia Modeling Mus Mutation Myeloid Progenitor Cells NUP98 gene National Cancer Institute Oncogenes Oncogenic Pattern Predictive Factor Prognosis Recurrence Regulation Role Sampling Testing Therapeutic Therapeutic Intervention Tumor Suppressor Proteins Untranslated RNA Up-Regulation acute lymphoblastic leukemia cell cancer initiation enhancer binding protein epigenome factor C in vivo leukemia leukemic transformation leukemogenesis novel novel therapeutic intervention nucleophosmin overexpression programs recruit therapeutic target trait transcription factor transcriptome translational medicine tumor progression

项目摘要

Project Summary An emerging body of literature has demonstrated the importance of non-coding DNA regulatory sequences in epigenetic and transcriptome regulation. Mutations of distal enhancers or enhancer binding proteins are identified as onco-drivers in a variety of cancers. They lead to deregulation of tumor suppressors and oncogenes, which in turn influence cancer initiation and progression. In our study, we propose to examine the function of transcription factor HOXA9 in enhancer regulation and how it may contribute to leukemogenesis. We will examine global changes in epigenome, with a focus on distal regulatory enhancers, in multiple acute myeloid and lymphoblastic leukemia models that have HOXA9 overexpression. We will identify recurrent HOXA9-dependent epigenetic alterations at distal enhancers and evaluate their potential as the therapeutic targets. We will also examine the mechanisms by which HOXA9 establishes open chromatin state at distal enhancers. Given extremely poor prognosis of acute leukemia with HOXA9 overexpression as well as the lack of good therapeutic options, in-depth mechanistic understanding of HOXA9 function in leukemogenesis will provide better options against the daunting clinical challenges. This project fits the mission of National Cancer Institute (NCI).

项目摘要一批新兴的文献证明了非编码DNA的重要性表观遗传和转录组调控中的调控序列。远端基因突变增强子或增强子结合蛋白在多种肿瘤中被确定为癌驱动因素癌症。它们导致对肿瘤抑制基因和癌基因的放松管制，进而影响癌症的发生和发展。在我们的研究中，我们建议研究转录因子HOXA9在增强子调控中的作用及其可能的作用与白血病的发生有关。我们将研究表观基因组的全球变化，重点放在远端调节增强剂，在多发性急性髓系白血病和淋巴母细胞白血病模型中 HOXA9基因过度表达。我们将确定复发的HOXA9依赖的表观遗传学并评估其作为治疗靶点的潜力。我们我还将研究HOXA9建立开放染色质状态在远端增强剂。鉴于HOXA9急性白血病预后极差过度表达以及缺乏良好的治疗选择，深入的机制了解HOXA9在白血病发生中的作用将为预防白血病提供更好的选择令人生畏的临床挑战。该项目符合国家癌症研究所的使命 (NCI)。