Novel Epigenetic Approaches in AML

组蛋白甲基转移酶、D0T1L和乙酰赖氨酸结合蛋白的研究进展 BRD4是急性髓系白血病(AML)亚群持续增殖和生存所必需的 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 D0T1L和BRD4的抑制剂已经被开发出来，并显示出显著的抗增殖活性 AML细胞为更深入地描述这些过程提供了进一步的理论基础。中心假说 对于这个项目来说，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、基因工程小鼠模型和遗传筛选。在具体目标1中，我们将 确定溴域抑制剂抑制Myc和E2F基因表达的机制 程序。在特定目标11中，我们将定义获得性小分子耐药性的机制 溴域抑制剂。这些研究将揭示临床耐药的可能机制。 治疗，并阐明这些分子通过哪些细胞途径抑制增殖和 诱导细胞凋亡。在具体目标3中，我们将评估令人信服的小分子抑制剂组合 表观遗传途径包括DOTI、L抑制剂和BET抑制剂的联合作用。鉴于我们有权访问 新开发的小分子抑制剂，建议的研究有可能带来新的，更多的 对被诊断为急性髓细胞白血病的儿童和成人有效、毒性较低的治疗方法。

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.