Exploiting the Context-Dependence of Notch to Develop Safer T-ALL therapy

利用 Notch 的上下文依赖性开发更安全的 T-ALL 疗法

• 批准号: 9889932
• 负责人: Anna Catherine McCarter
• 金额: $ 0.52万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889932
• 关键词: Acute Lymphocytic Leukemia; Acute T Cell Leukemia; Amino Acids; B-Lymphocytes; Binding; Biochemical; Cancer Etiology; Cell Line; Cell Nucleus; Cell membrane; Cells; Chemotherapy-Oncologic Procedure; Clinical Trials; Complex; DNA; Data; Dependence; Development; Disease; Dose; ETS1 gene; Enhancers; Epigenetic Process; Gene Expression; Genes; Genetic Transcription; Genomics; Homeostasis; Human; Impaired cognition; Impairment; Knock-out; Learning; Left; Leukemic Cell; Ligands; Malignant Neoplasms; Maps; Methods; Modeling; Modification; Mus; Mutation; NOTCH1 gene; Natural Killer Cells; Nature; Normal tissue morphology; Notch Signaling Pathway; Nuclear; Oncogenes; Oncogenic; Patients; Proteins; Public Health; Relapse; Research; Role; Safety; Sampling; Second Primary Cancers; Signal Transduction; Site; Structure; Survivors; T-Cell Development; T-Cell Proliferation; T-Lymphocyte; Therapeutic; Tissues; Toxic effect; Tumor Suppression; Tumor Suppressor Proteins; Validation; Withdrawal; Xenograft procedure; acute T-cell lymphoblastic leukemia cell; cell growth; cell type; childhood cancer mortality; clinically relevant; cofactor; combat; disability; druggable target; histone modification; inhibitor/antagonist; leukemia; mouse model; notch protein; novel; novel strategies; outcome forecast; recruit; side effect; targeted treatment; theories; transcription factor; transcriptome sequencing

PROJECT SUMMARY Despite advancements in standard chemotherapy regimens, acute lymphoblastic leukemia is still the leading cause of cancer death in children. Patients with relapsed T-cell acute lymphoblastic leukemia (T-ALL) have a particularly grim prognosis, and survivors develop long-term disabilities such as cognitive dysfunction and secondary cancers. Activating mutations in NOTCH1 have been implicated in more than 60% of patient T- cell acute lymphoblastic leukemias (T-ALL), giving hope for a targeted therapy in this disease. However, enthusiasm for pan-Notch inhibitors has been tempered by clinical trials showing that broad inhibition of Notch1 signaling results in treatment-limiting toxicities. The Notch signaling pathway is seemingly simple: ligand from a neighboring cell triggers proteolytic cleavage of the intracellular domain from the recipient cell's membrane. The intracellular domain is then free to translocate to the nucleus, where it associates with other cofactors to induce transcription of target genes involved in cellular growth and cell fate decisions. However, Notch signaling serves disparate functions in different tissues, even acting as an oncogene in some cancers while a tumor suppressor in others. What contributes to this pleotropic nature of Notch? A major contributor is the nuclear context. In T-ALL, Notch1 signaling promotes leukemic cell growth primarily through its activity at T-cell specific enhancers, which increase transcription of oncogenes, particularly MYC. Notch1 cannot activate these enhancers by itself; it requires other transcription factors to create a cell-type specific nuclear context that directs Notch1 to function. In theory, one could target the specific nuclear context that drives Notch in T- ALL in order to avoid the intolerable effects of pan-Notch inhibition. One factor that may promote T-cell specific Notch1 activity is Ets1. Ets1 is a highly conserved transcription factor involved in T-cell, B-cell, and NK-cell development. It has much more limited roles in normal tissue homeostasis than Notch. It is broadly and highly expressed in T-ALL and binds most Notch1-driven enhancers in a T-ALL cell line. This proposal's central hypothesis is that Ets1 drives the proliferation of T-ALL cells by enhancing Notch1 activity at oncogenic target genes. The first aim of the project utilizes primary human patient samples and mouse models of T-ALL to determine whether inhibition of Ets1 can safely and effectively treat T-ALL. The second aim of the project will use biochemical and genomic sequencing approaches to clarify the mechanism by which Ets1 enhances Notch1 target gene transcription. This proposal seeks to establish the potential of Ets1 inhibition as a therapeutic strategy for T-ALL, to identify the protein- protein interfaces required for the Ets1-Notch1 interaction, and to assess the impact of Ets1 loss on Notch1's recruitment to DNA, epigenetic modifications, and target gene transcription. By targeting the specific interactions responsible for oncogenic, context-dependent Notch1 signaling, it might be possible to inhibit Notch1 in cancer without the toxicity of pan-Notch inhibition.

项目摘要 尽管标准化疗方案取得了进展，但急性淋巴细胞白血病仍然是 儿童癌症死亡的主要原因。复发性T细胞急性淋巴细胞白血病（T-ALL）患者 预后特别糟糕，幸存者会发展成长期残疾，如认知功能障碍 和继发性癌症。NOTCH 1中的激活突变与超过60%的T- 细胞急性淋巴细胞白血病（T-ALL），为这种疾病的靶向治疗带来了希望。然而，在这方面， 对泛Notch抑制剂的热情已经被临床试验所缓和，临床试验显示， Notch 1信号传导导致治疗限制性毒性。Notch信号通路看起来很简单： 来自邻近细胞的配体触发来自受体细胞的胞内结构域的蛋白水解切割 膜的然后，细胞内结构域自由移位到细胞核，在那里它与其他细胞结合。 辅助因子诱导参与细胞生长和细胞命运决定的靶基因的转录。然而，在这方面， Notch信号在不同的组织中发挥不同的功能，甚至在某些癌症中充当致癌基因 而另一些则是肿瘤抑制因子。是什么促成了Notch的这种多效性？一个主要贡献者是 核背景。在T-ALL中，Notch 1信号主要通过其在白血病细胞中的活性促进白血病细胞生长。 T细胞特异性增强子，增加癌基因的转录，特别是MYC。Notch 1无法激活 这些增强子本身;它需要其他转录因子来创建细胞类型特异性核背景 控制Notch 1的功能从理论上讲，人们可以瞄准特定的核背景，驱动T中的Notch- ALL，以避免pan-Notch抑制的不可忍受的影响。 一个可能促进T细胞特异性Notch 1活性的因子是Ets 1。ets 1是一个高度保守的 参与T细胞、B细胞和NK细胞发育的转录因子。在正常情况下， 组织稳态比Notch。它在T-ALL中广泛且高度表达，并结合大多数Notch 1驱动的 T-ALL细胞系中的增强子。该提案的中心假设是Ets 1驱动T-ALL的增殖 通过增强致癌靶基因的Notch 1活性来增强细胞。该项目的第一个目标是利用初级 人类患者样品和T-ALL小鼠模型，以确定Ets 1的抑制是否可以安全和 有效治疗T-ALL。该项目的第二个目标将使用生物化学和基因组测序 阐明Ets 1增强Notch 1靶基因转录的机制。这项建议 试图建立Ets 1抑制作为T-ALL治疗策略的潜力，以鉴定蛋白质- Ets 1-Notch 1相互作用所需的蛋白质界面，并评估Ets 1缺失对Notch 1的影响。 DNA募集、表观遗传修饰和靶基因转录。通过针对特定的 相互作用负责致癌的，上下文依赖的Notch 1信号，它可能是可能的抑制 Notch 1在癌症中无毒性的泛Notch抑制。