权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanism of Notch-induced leukemogenesis in lymphocytes

Notch诱导淋巴细胞白血病发生的机制

基本信息

批准号：
8777092
负责人：
SUSAN M WINANDY
金额：
$ 17.8万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8777092
关键词：
Acute Lymphocytic Leukemia Acute T Cell Leukemia Address Apoptosis Biological Models Cell Line Cell Nucleus Cell Proliferation Cells Clinical Trials DNA Binding DNA-Binding Proteins Data Dependence Dependency Development Disease Drug Design Event Figs - dietary Gene Expression Generations Genes Goals Growth Health Hematopoietic Human Intervention Kinetics Lead Ligands Lymphocyte Mediating Modeling Molecular Mus Mutation Nuclear Oncogenes Oncogenic Pathway interactions Patients Play Process Proteins Regulation Role Signal Transduction Staging T-Cell Development T-Cell Leukemia T-Lymphocyte Testing Therapeutic Intervention Tissues Toxic effect Transcriptional Activation Tumor Suppressor Proteins cell type combat defined contribution design effective therapy gene therapy in vivo inhibitor/antagonist insight leukemia leukemogenesis mouse model new therapeutic target notch protein novel secretase

项目摘要

DESCRIPTION (provided by applicant): Notch receptors deliver signals that regulate cell fate decisions as well as other aspects of differentiation, proliferation and apoptosis for many different tissues and cell types. The active form of Notch, intracellular Notch (ICN), is generated by enzymatic cleavage events after interaction with Notch ligands on adjoining cells. ICN then translocates to the nucleus where it activates gene expression through interaction with the DNA binding protein, RBP-Jκ (RBPJ). Mutations that stabilize or result in ligand-independent generation of ICN are oncogenic in both mice and humans. Greater than 50% of T-acute lymphoblastic leukemia (T-ALL) in humans display oncogenic activation of Notch. Many mouse models exist that mirror this process, providing critical models with which to study mechanisms underlying both initiation and propagation of ICN-driven leukemia. Inhibitors that block Notch cleavage, γ-secretase inhibitors (GSIs), can suppress expression of ICN as well as proliferation of a subset of T-ALL cell lines, and therefore, have been tested in clinical trials. However, results of these trials have been disappointing due to limited anti-leukemic activity and toxicity issues. Therefore, understanding how oncogenic activation of Notch results in aggressive leukemia is of utmost importance to defining new targets for therapeutic intervention. Our preliminary data, using a novel cell line developed in our lab in which levels of Notch and RBPJ can be individually manipulated, suggest that GSIs do not mediate their growth inhibitory effects in T-ALL through abrogating RBPJ-dependent ICN-driven transcriptional activation. This suggests that ICN functions to promote leukemogenesis via a novel paradigm-challenging mechanism that does not require RBPJ. Therefore, the main focus of this proposal is to address the question: How does de-regulation of Notch lead to leukemia, and are there undefined mechanisms in play? We will explore both nuclear and extranuclear roles for ICN in maintaining proliferation of leukemia cells, as well as investigate the requirement for RBPJ in ICN-driven leukemogenesis initiated at multiple stages of T cell development in vivo. It is our hope that these studies will reveal new therapeutic targets for drug design or intervention for human leukemia.

描述(申请人提供)：Notch受体传递信号，调节细胞命运决定以及许多不同组织和细胞类型的分化、增殖和凋亡的其他方面。产生了Notch的活性形式--细胞内Notch(ICN 通过与相邻细胞上的Notch配体相互作用后的酶切割事件。然后，ICN转位到细胞核，在那里它通过与DNA结合蛋白RBP-Jκ(RBPJ)相互作用来激活基因表达。稳定或导致非配体依赖型ICN的突变在小鼠和人类中都是致癌的。在人类T-急性淋巴细胞白血病(T-ALL)中，超过50%的患者表现出Notch的致癌活性。存在许多反映这一过程的小鼠模型，为研究ICN驱动的白血病的启动和传播机制提供了关键的模型。阻断Notch裂解的抑制剂，γ分泌酶抑制剂(GSI)，可以抑制ICN的表达和T-ALL细胞亚群的增殖，因此已经在临床试验中进行了测试。然而，由于抗白血病活性有限和毒性问题，这些试验的结果令人失望。因此，了解Notch的致癌激活是如何导致侵袭性白血病的，对于确定治疗干预的新靶点至关重要。我们的初步数据，使用我们实验室开发的一种新的细胞系，其中Notch和RBPJ的水平可以单独操纵，表明GSI不通过取消依赖RBPJ的ICN驱动的转录激活来介导它们在T-ALL中的生长抑制作用。这表明ICN通过一种不需要RBPJ的新的挑战范式的机制来促进白血病的发生。因此，这项提案的主要焦点是解决这个问题：Notch的去调节如何导致白血病，是否有未明确的机制在起作用？我们将探索ICN在维持白血病细胞增殖中的核和核外作用，以及在体内T细胞发育的多个阶段开始的ICN驱动的白血病发生中对RBPJ的需求。我们希望这些研究将为人类白血病的药物设计或干预提供新的治疗靶点。