NPM-ALK & CD30 Signaling in Anaplastic Cell Lymphoma

描述(申请人提供)：间变性大细胞淋巴瘤(ALCL)占所有非霍奇金淋巴瘤的10%。ALCL均为CD30(+)，50%-60%的ALCL以t(2；5)易位为特征，在5号染色体上的核磷蛋白与2号染色体上的间变性淋巴瘤激酶(ALK)之间产生融合蛋白。NPM-ALK是一种激活多条信号转导途径的致癌酪氨酸激酶。当CD30被激活时，许多NPM-ALK(+)细胞株被证明经历了生长停滞。这一建议的目的是：1)确定哪些信号通路对转化至关重要，2)确定CD30如何调节NPM-ALK通路。为了实现这些目标，申请者将：1)确定NPM-ALK如何激活PI3K和STATS，2)确定PLC-β、PI3-激酶、STATS和支架蛋白在NPM-ALK诱导的小鼠骨髓移植模型中的淋巴瘤形成中的作用，3)确定CD30调节NPM-ALK信号通路的机制。这些研究将为NPM-ALK(+)淋巴瘤的生物学提供有价值的见解，可能导致新的治疗方式。 这位候选人在贝丝以色列女执事医疗中心完成了血液学和肿瘤学的学术奖学金，致力于学术医学的职业生涯，重点是转化性研究。拟议的五年学习课程将使候选人在免疫治疗和信号转导领域拥有广泛的经验，使他准备过渡到独立研究人员。

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.