BET bromodomain inhibition as targeted therapy in acute myeloid leukemia

描述（由申请人提供）：该项目的中心目标是了解BRD4作为急性髓性白血病治疗靶点的作用。作为染色质的调节因子，BRD4是一类新兴的抗癌药物靶点的成员，其治疗相关的分子功能知之甚少。本提案旨在通过确定BRD4在白血病细胞中使用的关键生化机制来解决这一问题，该机制解释了BRD4作为治疗靶点的理想特性。这将包括评估BRD4的哪些区域对其疾病相关功能最为关键，以及确定BRD4复合体的关键蛋白质成分，这些蛋白质成分是实验性小鼠模型中白血病维持所必需的。还将努力确定有效的治疗组合，可以与BRD4抑制剂协同抑制临床前白血病模型中的白血病进展。该项目将依靠综合方法，包括生化、遗传、蛋白质组学和表观基因组学策略。本研究将广泛使用化疗耐药白血病的基因工程小鼠模型，用于评估BRD4或其蛋白复合物组分的各种治疗操作的体内疗效。总之，本研究的长期目标将是通过了解BRD4蛋白作为染色质状态调节剂的详细机制，最大限度地提高靶向BRD4在白血病中的临床效益。

DESCRIPTION (provided by applicant): The central goal of this project is to understand the role of BRD4 as a therapeutic target in acute myeloid leukemia. As a regulator of chromatin, BRD4 is a member of an emerging class of anti-cancer drug targets for which little is understood of its therapeutically-relevant molecular function. This proposal seeks to address this issue by identifying the critical biochemical mechanism employed by BRD4 in leukemia cells that accounts for its desirable properties as a therapeutic target. This will include evaluating which regions of BRD4 are most crucial for its disease-related functions, as well as identifying the key protein constituents of the BRD4 complex that are necessary for leukemia maintenance in experimental mouse models. Efforts will also be made to identify effective therapeutic combinations that can synergize with BRD4 inhibitors to suppress leukemia progression in preclinical leukemia models. This project will rely on integrative approaches, including biochemical, genetic, proteomic, and epigenomic strategies. This research will make extensive use of genetically-engineered mouse models of chemotherapy-resistant leukemia, which will be used to evaluate the in vivo efficacy of various therapeutic manipulations of BRD4 or components of its protein complex. In summary, the long-term goal of this research will be to maximize the clinical benefit of targeting BRD4 in leukemia through an understanding of the detailed mechanism of how this protein works as a regulator of chromatin state.