The Kinomes of Non-Hodgkin Lymphoma

非霍奇金淋巴瘤的激酶组

• 批准号: 7291241
• 负责人: William Garrow Kerr
• 金额: $ 19.56万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7291241
• 关键词: B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Cell Cycle Regulation; Cells; Clinical; Detection; Diffuse Lymphoma; Disease; Emerging Technologies; Enzymes; Follicular Lymphoma; Gene Expression Profile; Genes; Goals; Growth; Immune response; Immunodeficient Mouse; Lymphoma; Molecular; Non-Hodgkin' s Lymphoma; Non-Malignant; Phase; Phosphorylation; Phosphotransferases; Play; Proliferating; Proteins; Proteome; Role; Serine; Signal Pathway; Signal Transduction; Site; Technology; Threonine; Tyrosine; angiogenesis; base; cancer cell; in vivo; in vivo Model; inhibitor/antagonist; insight; large cell Diffuse non-Hodgkin' s lymphoma; neoplastic cell; novel; tumor

DESCRIPTION (provided by applicant): Gene profiling technology has enabled analysis of the transcriptome and proteome of tumor cells. In fact, massively parallel analysis of the Non-Hodgkin Lymphoma (NHL) transcriptome has revealed discrete gene profile signatures for the major subtypes of NHL, diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). This information has provided useful insights into molecular mechanisms that promote enhanced survival and proliferation in NHL. However, an equally, if not more important goal, is to define those proteins that participate in signaling pathways active in lymphoma cells and non-malignant cells that infiltrate these tumors. Enzymes that phosphorylate tyrosine, serine and threonine residues on other proteins play a major role in signaling cascades that control cell cycle entry, survival, angiogenesis and the immune response. Defining how these signaling pathways are altered in NHL B cells and non- malignant cells present in these tumors will provide critical information for understanding how lymphoma survives, proliferates and interacts with other cells at the tumor site. We are applying to purified tumor cells a novel array strategy that allows the simultaneous detection of phosphorylation for 1152 different kinase substrates. Here we propose to apply this emerging technology to the analysis of phosphorylation-based cell signaling pathways in NHL. This proposal will be pursued in two phases. The R21 phase will consist of two aims that will validate PepChip technology can identify kinome alterations in primary DLBCL (Aim 1) and FL (Aim 2) isolates. The R33 phase will consist of two aims that will define kinome alterations in DLBCL (Aim 3) and FL (Aim 4) that correlate with clinical parameters. In Aim 5 we will utilize in vivo models of FL and DLBCL to determine whether inhibitors specific for deregulated kinases inhibit growth of NHL tumors in immunodeficient mice. This study will be pursued in the following phased R21/R33 format: R21 Phase: Aim 1: Define the kinome of DLBCL B cells and non-malignant cells present in these tumors. Aim 2: Define the kinome of FL B cells and non-malignant cells present in these tumors. Aim 3: Identify kinome alterations in DLBCL correlated with clinical parameters of disease. R33 Phase: Aim 4: Identify kinome alterations in FL correlated with clinical parameters of disease. Aim 5: Determine whether deregulated kinases contribute to NHL growth in vivo.

描述（由申请人提供）：基因谱分析技术已经能够分析肿瘤细胞的转录组和蛋白质组。事实上，非霍奇金淋巴瘤（NHL）转录组的大规模平行分析揭示了NHL主要亚型、弥漫性大B细胞淋巴瘤（DLBCL）和滤泡性淋巴瘤（FL）的离散基因谱特征。这些信息提供了有用的见解，促进增强生存和增殖的NHL的分子机制。然而，一个同等的，如果不是更重要的目标，是定义那些蛋白质，参与信号通路的淋巴瘤细胞和非恶性细胞浸润这些肿瘤中活跃。磷酸化其他蛋白质上的酪氨酸、丝氨酸和苏氨酸残基的酶在控制细胞周期进入、存活、血管生成和免疫应答的信号级联中起主要作用。确定这些信号通路如何在NHL B细胞和存在于这些肿瘤中的非恶性细胞中改变，将为理解淋巴瘤如何存活、增殖和与肿瘤部位的其他细胞相互作用提供关键信息。我们将一种新的阵列策略应用于纯化的肿瘤细胞，该策略允许同时检测1152种不同激酶底物的磷酸化。在这里，我们建议将这一新兴技术的磷酸化为基础的细胞信号通路在NHL的分析。这项建议将分两个阶段执行。R21阶段将包括两个目标，这两个目标将验证PepChip技术可以识别原发性DLBCL（Aim 1）和FL（Aim 2）分离株中的激酶组改变。R33阶段将由两个目标组成，这两个目标将定义DLBCL（目标3）和FL（目标4）中与临床参数相关的激酶组改变。在目标5中，我们将利用FL和DLBCL的体内模型来确定对失调激酶特异性的抑制剂是否抑制免疫缺陷小鼠中NHL肿瘤的生长。本研究将以以下阶段性R21/R33形式进行：R21阶段：目标1：确定这些肿瘤中存在的DLBCL B细胞和非恶性细胞的激酶组。目的2：确定FL B细胞和这些肿瘤中存在的非恶性细胞的激酶组。目的3：确定DLBCL中与疾病临床参数相关的激酶组改变。R33阶段：目的4：确定FL中与疾病临床参数相关的激酶组改变。目的5：确定是否失调激酶有助于NHL生长在体内。