NPM-ALK & CD30 Signaling in Anaplastic Cell Lymphoma

NPM-ALK

• 批准号: 6688328
• 负责人: HENRY B KOON
• 金额: $ 13.03万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-17 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6688328
• 关键词: CD antigens; biological signal transduction; cell line; enzyme activity; enzyme induction /repression; flow cytometry; gel mobility shift assay; gene targeting; genetically modified animals; immunoprecipitation; laboratory mouse; luciferin monooxygenase; neoplastic transformation; nonHodgkin' s lymphoma; oncoprotein p21; phosphatidylinositol 3 kinase; phospholipase C; phosphorylation; protein protein interaction; protein structure function; protein tyrosine kinase; site directed mutagenesis; transfection /expression vector; western blottings

DESCRIPTION (provided by applicant): Anaplastic Large Cell Lymphoma (ALCL) comprises 10% of all non-Hodgkin's lymphoma. ALCL are uniformly CD30 (+) and 50-60% of ALCL are characterized by the t (2;5) translocation which produces a fusion protein between Nucleophosmin on chromosome 5 and Anaplastic Lymphoma Kinase (ALK) on chromosome 2. NPM-ALK is an oncogenic tyrosine kinase that activates multiple signal transduction pathways. A number of NPM-ALK (+) cell lines have been shown to undergo growth arrest when CD30 is activated. The goal of this proposal is to: 1) determine which signaling pathways are critical for transformation, and 2) determine how CD30 modulates NPM-ALK pathways. To accomplish these goals the applicant will: 1) Determine how NPM-ALK activates PI3K and the STATs, 2) Determine the role of PLC-?, PI3-kinase, STATs and scaffolding proteins in NPM-ALK induced lymphomagenesis in a murine bone marrow transplant model, 3) Determine the mechanism by which CD30 modulates NPM-ALK signaling pathways. These studies will provide valuable insight into the biology of NPM-ALK (+) lymphomas that may lead to new therapeutic modalities. The candidate, who completed an academic Hematology-Oncology fellowship at Beth Israel Deaconess Medical Center, is committed to a career in academic medicine with an emphasis in translational research. The proposed five-year course of study will give the candidate a broad experience in fields of immunotherapy and signal transduction leaving him prepared to make the transition to independent investigator.

描述（由申请人提供）：肿瘤大型细胞淋巴瘤（ALCL）占所有非霍奇金淋巴瘤的10％。 ALCL是统一的CD30（+）和50-60％的ALCL的特征，其特征是T（2;​​ 5）易位，该易位在5号染色体上产生融合蛋白，在5号染色体上的核酚蛋白和染色体上的变性淋巴瘤激酶（ALK）上的染色体2。npm-alk。NPM-alk。 当激活CD30时，已显示许多NPM-ALK（+）细胞系会发生生长停滞。 该建议的目的是：1）确定哪些信号通路对于转换至关重要，2）确定CD30如何调节NPM-Alk途径。 为了实现这些目标，申请人将：1）确定NPM-Alk如何激活PI3K和统计数据，2）确定PLC-？，PI3-激酶，PI3-激酶，统计数据和脚手架蛋白在NPM-Alk诱导的淋巴结型在鼠骨Marrow Transplant模型中的淋巴结诱导的淋巴结型，3）确定cd30 npm的机械途径。 这些研究将为可能导致新的治疗方式的NPM-Alk（+）淋巴瘤的生物学提供宝贵的见解。 候选人在贝丝以色列执事医学中心完成了学术血液肿瘤学奖学金，他致力于从事学术医学职业，重点是转化研究。 拟议的五年研究课程将使候选人在免疫疗法和信号转导领域具有广泛的经验，使他准备过渡到独立研究者。