Novel Epigenetic Approaches in AML

最近的研究表明，组蛋白甲基转移酶D0T1L和乙酰赖氨酸结合蛋白 BRD4是急性骨髓性白血病（AML）亚群持续增殖和存活所必需的 细胞指出表观遗传机制是这种疾病的潜在治疗靶点。小分子 已经开发了D0T1L和BRD4的抑制剂，并显示出显著的抗增殖活性， AML细胞为这些过程的更深入表征提供了进一步的理论依据。核心假设 该项目的一个重要目标是表观遗传机制的小分子抑制剂将有效地靶向AML细胞。我们 将通过使用新的小分子，化学生物学方法， 表观基因组分析遗传工程小鼠模型和遗传筛选。在具体目标1中， 定义布罗莫结构域抑制剂抑制Myc和E2F驱动的基因表达的机制 程序.在具体目标11中，我们将定义对小分子药物的获得性耐药机制。 布罗莫结构域抑制剂。这些研究将为临床耐药性的可能机制提供信息， 治疗，并阐明这些分子通过其抑制增殖和 诱导细胞凋亡。在具体目标3中，我们将评估以下药物的小分子抑制剂的令人信服的组合： 表观遗传途径，包括DOTIL抑制剂和BET抑制剂的组合。鉴于我们能接触到 新开发的小分子抑制剂，拟议的研究有可能带来新的，更多的 有效的，毒性较小的治疗，以儿童和成人诊断为AML。

The recent demonstration that the histone methyltransferase, D0T1L and the acetylysine binding protein BRD4 are required for continued proliferation and survival for subsets of acute myelogenous leukemia (AML) cells points to epigenetic mechanisms as potential therapeutic targets in this disease. Small molecule inhibitors of D0T1L and BRD4 have been developed and show remarkable antiproliferative activity against AML cells providing further rationale for deeper characterization of these processes. The central hypothesis for this project is that small molecule inhibitors of epigenetic mechanisms will effectively target AML cells. We will assess this hypothesis through the use novel small molecules, chemical biological approaches, epigenomic analyses genetically engineered mouse models and genetic screens. In specific Aim 1 we will define the mechanisms by which bromodomains inhibitors suppress Myc and E2F driven gene expression programs. In specific Aim 11 we will define mechanisms of acquired resistance to small molecule bromodomain inhibitors. These studies will inform as to possible mechanisms of clinical resistance to such therapies, and illuminate the cellular pathways through which these molecules suppress proliferation and induce apoptosis. In specific aim 3 we will assess compelling combinations of small molecule inhibitors of epigenetic pathways including the combination of DOTI L inhibitors and BET inhibitors. Given our access to newly developed small molecule inhibitors, the proposed studies have the potential to bring new, more efficacious, less toxic therapies to children and adults diagnosed with AML.