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的分子机制， 制定创新的治疗策略，以提高患有难治性癌症的儿童的生存率 如AML。该项目的目标是实现这一目标的下一个合乎逻辑的步骤， 我们的U 54合作联盟，是定义和治疗靶向致癌基因， NUP 98融合蛋白复合物在AML中的表达控制活性。我们的核心假设是， NUP 98融合蛋白产生致癌染色质重塑蛋白复合物，其诱导 致白血病基因表达，赋予异常白血病细胞生长和存活， 分子机制和治疗靶点可以使用以下创新的整合来定义： 功能基因组学和蛋白质组学。这一假设是基于两个基本的初步研究 阿姆斯特朗实验室（Armstrong labs）和阿维尼翁实验室最近完成的研究（3，6），为这一研究提供了动力。 项目：1）发现NUP 98融合蛋白与细胞间的重要功能相互作用， AML中的MLL 1和NSL染色质重塑复合物;和2）制定策略， 细胞蛋白质复合物的结构和治疗性分解。然而，精确 NUP 98融合蛋白复合物组装与致白血病染色质功能的相关机制 没有定义，这构成了一个重要的知识空白， 合理的治疗策略来治疗融合癌蛋白激活的AML。目标1将阐明 利用NUP 98融合蛋白的可诱导降解进行白血病发生的染色质重塑的机制 proteins.在目标2中，我们将定义参与异常组装的结构域和界面。 NUP 98-融合染色质重塑复合物，使用原位交联质谱法， CRISPR结构域扫描。最后，我们将确定靶向的抗白血病疗效。 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 这一建议有望揭示NUP 98融合的分子机制和有效的治疗方法 癌蛋白和基因控制AML，从而提供了一个基本的问题， 这一点我们仍然知之甚少。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导致大多数人类癌症。最后 与U 54联盟中其他项目的互补互动， 在AML中靶向NUP 98融合蛋白的分子疗法将构成一种变革性的 对这种疾病患者的临床护理取得进展，其治愈率仍然完全不足 目前的治疗。