Enhancer Dysregulation in AML

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)。

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).