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

• 批准号: 7081151
• 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
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7081151
• 关键词: acute lymphocytic leukemia; gene mutation; human

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，在55％的人类T-ALL患者样本中激活Notch1突变。这些新发现的突变分布在两个热点之间 - 异二聚化（HD）和害虫域。但是，每个突变的相对重要性和后果仍然未知且未探索。我的初步研究表明，除非在顺es中的害虫热点发生第二个突变，否则HD热点中的单个激活突变不能诱导小鼠的T-All。我将通过确定所有HD突变是否需要并发的虫害突变并确定T-All多步发病机理期间的合作致癌基因，并确定所有HD突变。为了了解Notch启动和维持肿瘤发生的分子机制，我将表征Notch抑制对白血病细胞系的增殖，存活和分化的影响，并使用此信息来开发一种系统的策略来测试由微阵列数据集产生的推定靶基因。这些研究不仅应提高对T-All发病机理的了解，还应确定新的治疗策略。 该建议描述了一项为期5年的培训计划，以发展癌症生物学的学术生涯。该提案中描述的实验将在沃伦·皮尔（Warren Pear）博士的指导下使用和操纵鼠类遗传模型系统的使用和操纵来提供宝贵的经验。 Pear博士是Abramson家族癌症研究所的副教授，在操纵和分析白血病模型方面拥有丰富的经验。最终，在该项目的开发中花费的时间将在白血病学领域建立询问线，并将提供必要的技能，使自己成为成功的医师科学家和独立研究人员。 急性T细胞淋巴细胞白血病仍然是儿童和成人的致命癌症，在每三到四名患者中，不能治愈一个以上。最近的一项突破性研究确定了大多数该癌症患者的Notch1突变。我的研究试图揭示这些突变的重要性以及该突变引起的细胞中引起癌症的分子事件的重要性，这可能为治疗提供了新的机会。