NPM-ALK & CD30 Signaling in Anaplastic Cell Lymphoma

描述（由申请人提供）：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CD 30（+），50-60%的ALCL特征为t（2;5）易位，在5号染色体上的核磷蛋白和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是一种致癌酪氨酸激酶，可激活多种信号转导途径。 已经证明，当CD 30活化时，许多NPM-ALK（+）细胞系发生生长停滞。 本提案的目标是：1）确定哪些信号通路对转化至关重要，2）确定CD 30如何调节NPM-ALK通路。 为了实现这些目标，申请人将：1）确定NPM-ALK如何激活PI 3 K和STAT，2）确定PLC-？的作用，在鼠骨髓移植模型中NPM-ALK诱导的淋巴瘤发生中的PI 3-激酶、STAT和支架蛋白。3）确定CD 30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。 该候选人在Beth Israel Deaconess Medical Center完成了学术血液学肿瘤学奖学金，致力于学术医学的职业生涯，重点是转化研究。 拟议的五年学习课程将为候选人提供免疫治疗和信号转导领域的广泛经验，使他准备过渡到独立研究者。

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.