Enhancer Dysregulation in AML

AML 中的增强子失调

• 批准号: 9882974
• 负责人: Yali Dou
• 金额: $ 20.65万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9882974
• 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; Lead; 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; Recurrence; Regulation; Role; Sampling; Testing; Therapeutic; Therapeutic Intervention; Tumor Suppressor Proteins; Untranslated RNA; Up-Regulation; acute lymphoblastic leukemia cell; base; cancer initiation; enhancer binding protein; epigenome; factor C; in vivo; leukemia; leukemic transformation; leukemogenesis; novel; novel therapeutic intervention; nucleophosmin; outcome forecast; overexpression; programs; recruit; therapeutic target; trait; transcription factor; transcriptome; translational medicine; tumor progression

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 一个新兴的文学机构已经证明了非编码DNA的重要性 表观遗传和转录组调控中的调控序列。远端突变 增强子或增强子结合蛋白被鉴定为多种肿瘤驱动因子， 癌的它们导致肿瘤抑制因子和癌基因的失调， 影响癌症发生和发展。在我们的研究中，我们建议检查 转录因子HOXA 9在增强子调控中的功能及其作用 到白血病我们将研究表观基因组的全球变化，重点是远端 调节增强剂，在多发性急性髓细胞和淋巴细胞白血病模型中， HOXA 9过表达。我们将确定复发性HOXA 9依赖性表观遗传 在远端增强子的改变，并评估其作为治疗靶点的潜力。我们 我们还将研究HOXA 9建立开放染色质状态的机制， 远端增强子。考虑到HOXA 9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HOXA 9在白血病发生中的功能将提供更好的选择， 令人生畏的临床挑战该项目符合美国国家癌症研究所的使命 （NCI）。