Mechanism of Notch-induced leukemogenesis in lymphocytes

Notch诱导淋巴细胞白血病发生的机制

• 批准号: 8637293
• 负责人: SUSAN M WINANDY
• 金额: $ 22.63万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 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/8637293
• 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; Flowcharts; Gene Expression; Generations; Genes; Goals; Growth; 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; public health relevance; secretase

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-J? (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, ?-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（由申请人提供）：Notch受体传递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的信号。产生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裂解事件。ICN然后易位到细胞核，在那里它通过与DNA结合蛋白RBP-J相互作用激活基因表达。（RBPJ）。稳定或导致ICN的配体非依赖性产生的突变在小鼠和人类中都具有致癌性。超过50%的人类T-急性淋巴细胞白血病（T-ALL）显示Notch的致癌激活。许多小鼠模型反映了这一过程，为研究ICN驱动的白血病的启动和传播机制提供了关键模型。阻断Notch裂解的抑制剂，分泌酶抑制剂（GSI）可以抑制ICN的表达以及T-ALL细胞系亚群的增殖，因此，已经在临床试验中进行了测试。然而，由于有限的抗白血病活性和毒性问题，这些试验的结果令人失望。因此，了解Notch的致癌激活如何导致侵袭性白血病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不介导其生长抑制作用在T-ALL通过废除RBPJ依赖ICN驱动的转录激活。这表明，ICN的功能，以促进白血病通过一种新的范式挑战机制，不需要RBPJ。因此，该提案的主要焦点是解决以下问题：Notch的失调如何导致白血病，以及是否存在未定义的机制？我们将探讨ICN在维持白血病细胞增殖中的核和亚核作用，以及研究在体内T细胞发育的多个阶段启动的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揭示新的治疗靶点。