Project 2

项目2

• 批准号: 10230528
• 负责人: Charles G. Mullighan
• 金额: $ 2.56万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10230528
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Adult; Architecture; Biological Markers; Cell Survival; Child; Chimeric Proteins; Chromatin; Chromatin Remodeling Factor; Clustered Regularly Interspaced Short Palindromic Repeats; Combination Drug Therapy; Dependence; Development; Disease; Epigenetic Process; Experimental Models; Fusion Oncogene Proteins; Gene Expression; Gene Expression Regulation; Gene Mutation; Genes; Genetic; Genetic Transcription; Goals; Human; In Situ; Knowledge; Leukemic Cell; Link; MLL gene; Malignant Neoplasms; Mass Spectrum Analysis; Mission; Molecular; Mutation; NUP98 gene; Oncogenic; Outcome; Patient Care; Patients; Pharmacology; Pre-Clinical Model; Proteins; Proteomics; Public Health; Refractory; Relapse; Research; Research Project Grants; Resistance; Scanning; Stem cell transplant; Technology; Therapeutic; Translating; United States National Institutes of Health; Xenograft procedure; base; cell growth; chemotherapy; chromatin remodeling; clinical care; cohort; crosslink; effective therapy; functional genomics; fusion gene; improved; innovation; insight; leukemia; leukemogenesis; molecular targeted therapies; mouse model; novel; novel strategies; pre-clinical; prospective; protein complex; therapeutic target; transcription factor; treatment strategy

Our long-term goal is to elucidate molecular mechanisms of aberrant gene control in cancer and develop innovative treatment strategies to improve the survival of children with refractory cancers such as AML. The objective of this project, which is the next logical step towards this goal as part of our collaborative U54 consortium, is to define and therapeutically target the oncogenic gene expression control activity of NUP98 fusion protein complex in AML. Our central hypothesis is that NUP98 fusion proteins generate an oncogenic chromatin remodeling protein complex that induces leukemogenic gene expression, conferring aberrant leukemia cell growth and survival, and that its molecular mechanisms and therapeutic targets can be defined using an innovative integration of functional genomics and proteomics. This hypothesis is based on two essential preliminary studies that the Armstrong and Kentsis labs have recently completed (3, 6), providing the impetus for this project: 1) Discovery of the essential functional interaction between NUP98 fusion proteins and the MLL1 and NSL chromatin remodeling complexes in AML; and 2) development of strategies to define the architecture and therapeutic disassembly of cellular protein complexes. However, the precise mechanisms linking NUP98 fusion protein complex assembly and leukemogenic chromatin functions are not defined, constituting an important gap in knowledge that is required for the development of a rational therapeutic strategy to treat fusion oncoprotein-activated AML. Aim 1 will elucidate the mechanisms of leukemogenic chromatin remodeling using inducible degradation of NUP98-fusion proteins. In Aim 2, we will define the domains and interfaces involved in aberrant assembly of NUP98-fusion chromatin remodeling complexes using in situ cross-linking mass spectrometry and CRISPR domain scanning. And lastly, we will determine the anti-leukemia efficacy of targeted epigenetic and protein interaction therapies using preclinical mouse models. Successful completion of this proposal is expected to yield molecular mechanisms and effective therapies of NUP98 fusion oncoprotein and gene control in AML, thus providing essential insights into a fundamental problem that remains poorly understood. This research will have broad significance because fusion oncoproteins and oncogenic gene expression contribute to the majority of human cancers. Finally, the complementary interactions with other projects in this U54 consortium and development of effective molecular therapies targeting NUP98 fusion proteins in AML would constitute a transformative advance in the clinical care of patients with this disease, whose cure rates remain wholly inadequate with current therapy.

我们的长期目标是阐明癌症中异常基因控制和 制定创新的治疗策略，以改善难治性癌症儿童的生存 例如AML。该项目的目的，这是朝着该目标迈出的下一个逻辑步骤 我们的协作U54联盟是定义和治疗靶向致癌基因 NUP98融合蛋白复合物在AML中的表达控制活性。我们的中心假设是 NUP98融合蛋白会产生一种致癌染色质重塑蛋白复合物，可诱导 白血病基因表达，赋予异常白血病细胞的生长和生存，并具有 可以通过创新的整合来定义分子机制和治疗靶标 功能基因组学和蛋白质组学。该假设基于两项基本初步研究 阿姆斯特朗和肯特斯实验室最近已经完成（3，6），为此提供了动力 项目：1）发现NUP98融合蛋白与 AML中的MLL1和NSL染色质重塑复合物； 2）制定定义的策略 细胞蛋白复合物的结构和治疗性分解。但是，确切的 连接NUP98融合蛋白复合物组装和白血病染色质功能的机制 没有定义，构成了开发一个知识的重要差距 治疗融合量蛋白激活的AML的理性治疗策略。 AIM 1将阐明 使用NUP98融合的诱导降解的白血病染色质重塑的机制 蛋白质。在AIM 2中，我们将定义与异常组装相关的域和接口 NUP98融合染色质重塑复合物，使用原位交联质谱法和 CRISPR域扫描。最后，我们将确定目标的抗白血病功效 使用临床前小鼠模型的表观遗传和蛋白质相互作用疗法。成功完成 该建议有望产生分子机制和NUP98融合的有效疗法 AML中的癌蛋白和基因控制，从而为基本问题提供了基本见解 那仍然很熟悉。这项研究将具有广泛的意义，因为融合 癌蛋白和致癌基因表达有助于大多数人类癌症。最后， 在U54财团中与其他项目的互补互动和有效的发展 靶向NUP98融合蛋白AML中的分子疗法将构成变革性 在这种疾病的患者的临床护理中，他们的治愈率仍然完全不足 目前的疗法。