Targeting the B Cell Receptor Signaling Network in Lymphoma

6.项目总结/摘要 本项目的目标是剖析B细胞受体（BCR）信号网络采用的机制， 在健康的B细胞中控制着细胞的生死功能，决定着BCR信号网络是如何 在三种BCR信号异常的癌症中重塑，然后通过识别恶性B细胞， 并瞄准那些生存所需的机制。技术的组合，包括 通过流式细胞术和计算机辅助测量来自原代人组织的单个细胞中的信号传导 BCR信令网络的建模，将用于实现这一目标。 信号转导在健康免疫细胞的发育和细胞重塑中起着关键作用， 信号传导机制驱动肿瘤细胞增殖并抑制凋亡，有助于肿瘤存活 尽管有强烈的治疗方案。在B细胞非霍奇金淋巴瘤中，通过B细胞抗原的信号传导 受体可能特别可能支持恶性B细胞，因为BCR信号传导通常控制存活， 细胞凋亡和整个发育和分化中的增殖。这个项目的核心假设是 异常BCR信号是淋巴瘤B细胞存活所必需的。 我之前已经证明，人类癌症标本中的信号可以在单个细胞水平上绘制 通过流式细胞术，并使用这种技术来鉴定癌细胞特异性BCR信号转导的改变， 原发性人类淋巴瘤标本。在这里，我建议整合这种单细胞信号传导模式的方法 通过测量信号传导的功能结果，包括细胞死亡、增殖和基因表达， 表情具体目标是（I）识别对比功能所需的BCR信号机制 - 凋亡和增殖-在健康人B细胞的五个阶段，（II）鉴定异常BCR信号传导 在三种成熟B细胞淋巴瘤中的活性，并确定每种疾病的独特信号传导特征，和（III） 鉴定淋巴瘤B细胞存活所需的异常BCR信号传导事件并靶向这些事件 特异性杀死淋巴瘤细胞的事件 该项目将通过首先澄清我们对信号转导如何 通常控制细胞行为，然后通过将这种机械的见解转化为对 恶性B细胞信号网络中的关键“机会目标”。

6. PROJECT SUMMARY/ABSTRACT The goal of this project is to dissect which mechanisms the B cell receptor (BCR) signaling network employs to govern life and death cellular functions in healthy B cells, determine how the BCR signaling network is remodeled in three types of cancer with abnormal BCR signaling, and then kill malignant B cells by identifying and targeting those mechanisms which are required for survival. A combination of technologies, including measurement of signaling in individual cells from primary human tissues by flow cytometry and computational modeling of the BCR signaling network, will be used to achieve this goal. Signal transduction plays a key role in the development of healthy immune cells, and remodeling of cell signaling mechanisms drives tumor cell proliferation and suppresses apoptosis, contributing to tumor survival despite intense therapy regimens. In B cell non-Hodgkin's lymphomas, signaling through the B cell antigen receptor might be especially likely to support malignant B cells, as BCR signaling normally controls survival, apoptosis, and proliferation throughout development and differentiation. The central hypothesis of this project is that abnormal BCR signaling is required for the survival of lymphoma B cells. I have previously shown that signaling in human cancer specimens can be mapped at the individual cell level by flow cytometry and used this technology to identify cancer-cell specific alteration of BCR signaling in primary human lymphoma specimens. Here, I propose to integrate this single cell signaling profile approach with measurements of the functional outcomes of signaling, including cell death, proliferation, and gene expression. The Specific Aims are to (I) identify BCR signaling mechanisms required for contrasting functions - apoptosis and proliferation - in five stages of healthy human B cells, (II) identify abnormal BCR signaling activity in three mature B cell lymphomas and determine unique signaling features of each disease, and (III) identify abnormal BCR signaling events that are required for survival of lymphoma B cells and target these events to specifically kill lymphoma cells This project will advance cancer research by first clarifying our understanding of how signal transduction normally governs cell behavior and then by translating this mechanistic insight into a sharp understanding of critical 'targets of opportunity' in the signaling networks of malignant B cells.