Significance of mutations in human NOTCH1 in T cell acute lymphoblastic leukemia

人NOTCH1突变在T细胞急性淋巴细胞白血病中的意义

基本信息

批准号：
7653806
负责人：
MARK Y CHIANG
金额：
$ 13.33万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7653806
关键词：
Acute T Cell Leukemia Adult Alleles Animal Model Biological Models Bite C-terminal Cancer Biology Cancer Etiology Candidate Disease Gene Cell Line Cell Nucleus Cell membrane Cells Cessation of life Child Chromosomal translocation Classification Complex Data Data Set Development Dominant-Negative Mutation Drosophila genus Event Family Funding Gene Targeting Genetic Models Goals Hematopoietic Hematopoietic stem cells Heterodimerization Histocompatibility Testing Homologous Gene Human Lead Leukemic Cell Life Ligands Malignant Neoplasms Measures Mediating Mentorship Microarray Analysis Modeling Molecular Mus Mutate Mutation NOTCH1 gene Oncogenes Oncogenic Pathogenesis Patients Pear Phenotype Physicians Relative (related person)Research Research Institute Research Personnel Role Sampling Scientist Signal Pathway Signal Transduction TAL1 gene TLX1 gene Testing Time Training Programs anticancer research career cell growth experience follow-up gain of function mutation improved inhibitor/antagonist leukemogenesis malignant phenotype mutant neoplastic notch protein novel therapeutics professor progenitor receptor research study skills small molecule synergism transcription factor treatment strategy tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): A recent study found activating Notch1 mutations in 55% of human T-ALL patient samples. These newly discovered mutations are distributed among two hotspots -- the heterodimerization (HD) and PEST domains. However, the relative importance and consequence of each mutation remains unknown and unexplored. My preliminary research suggests that a single activating mutation in the HD hotspot cannot induce T-ALL in mice unless a second mutation occurs in the PEST hotspot in cis. I will follow up on these observations by determining whether all HD mutations require concurrent PEST mutations and by identifying cooperating oncogenes during the multi-step pathogenesis of T-ALL. In order to understand the molecular mechanism by which Notch initiates and sustains oncogenesis, I will characterize the effect of Notch inhibition on the proliferation, survival, and differentiation of leukemic cell lines and use this information to develop a systematic strategy for testing putative target genes generated from microarray data sets. Together these studies should not only lead to an improved understanding of T-ALL pathogenesis but will also identify novel therapeutic strategies for treatment. This proposal describes a 5 year training program to develop an academic career in cancer biology. The experiments described in the proposal will provide valuable experience in the use and manipulation of murine genetic model systems for the study of cancer under the mentorship of Dr. Warren Pear. Dr. Pear is an associate professor at the Abramson Family Cancer Research Institute with extensive experience in the manipulation and analysis of animal models of leukemogenesis. Ultimately, the time spent in the development of this project will establish a line of inquiry in the field of leukemogenesis and will provide the skills necessary to establish myself as a successful physician scientist and independent researcher. Acute T cell lymphoblastic leukemia remains a deadly cancer in children and adults which cannot be cured in more than one out of every three to four patients. A recent breakthrough study has identified Notch1 mutations in the majority of patients with this cancer. My research seeks to uncover the significance of these mutations and the cancer-causing molecular events in the cell that are triggered by this mutation, which may provide new opportunities for therapy.

描述（由申请人提供）：最近的一项研究发现，55% 的人类 T-ALL 患者样本中存在激活 Notch1 突变。这些新发现的突变分布在两个热点——异二聚化（HD）和 PEST 域。然而，每个突变的相对重要性和后果仍然未知和未经探索。我的初步研究表明，HD 热点中的单个激活突变不能诱导小鼠发生 T-ALL，除非顺式 PEST 热点中发生第二个突变。我将通过确定所有 HD 突变是否都需要同时发生 PEST 突变并确定 T-ALL 多步骤发病机制中的协同癌基因来跟进这些观察结果。为了了解 Notch 启动和维持肿瘤发生的分子机制，我将描述 Notch 抑制对白血病细胞系增殖、存活和分化的影响，并利用这些信息制定系统策略来测试生成的假定靶基因来自微阵列数据集。这些研究不仅可以增进对 T-ALL 发病机制的了解，而且还将确定新的治疗策略。该提案描述了一个为期 5 年的培训计划，旨在发展癌症生物学的学术生涯。该提案中描述的实验将为在 Warren Pear 博士的指导下使用和操作小鼠遗传模型系统来研究癌症提供宝贵的经验。 Pear 博士是艾布拉姆森家族癌症研究所的副教授，在白血病发生动物模型的操作和分析方面拥有丰富的经验。最终，开发该项目所花费的时间将在白血病发生领域建立一条探究路线，并将提供使我自己成为一名成功的医师科学家和独立研究员所需的技能。急性 T 细胞淋巴细胞白血病仍然是儿童和成人中一种致命的癌症，超过三到四名患者中就有一人无法治愈。最近的一项突破性研究发现大多数这种癌症患者存在 Notch1 突变。我的研究旨在揭示这些突变的重要性以及由这种突变引发的细胞中致癌分子事件，这可能为治疗提供新的机会。