The Kinomes of Non-Hodgkin Lymphoma

非霍奇金淋巴瘤的激酶组

• 批准号: 7493071
• 负责人: William Garrow Kerr
• 金额: $ 13.24万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7493071
• 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（申请人提供）：基因图谱技术已经能够分析肿瘤细胞的转录组和蛋白质组。事实上，对非霍奇金淋巴瘤 (NHL) 转录组的大规模并行分析揭示了 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。这些信息为促进 NHL 生存和增殖的分子机制提供了有用的见解。然而，一个同样重要（如果不是更重要）的目标是定义那些参与淋巴瘤细胞和浸润这些肿瘤的非恶性细胞中活跃的信号通路的蛋白质。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、血管生成和免疫反应的信号级联中发挥着重要作用。定义 NHL B 细胞和这些肿瘤中存在的非恶性细胞中这些信号传导途径如何改变，将为了解淋巴瘤如何存活、增殖以及与肿瘤部位的其他细胞相互作用提供关键信息。我们正在将一种新颖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，我们建议将这种新兴技术应用于 NHL 中基于磷酸化的细胞信号通路的分析。该提案将分两个阶段进行。 R21 阶段将包括两个目标，验证 PepChip 技术能否识别原发性 DLBCL（目标 1）和 FL（目标 2）分离株中的激酶组改变。 R33 阶段将包括两个目标，定义与临床参数相关的 DLBCL（目标 3）和 FL（目标 4）的激酶组改变。在目标 5 中，我们将利用 FL 和 DLBCL 的体内模型来确定针对失调激酶的特异性抑制剂是否能抑制免疫缺陷小鼠中 NHL 肿瘤的生长。这项研究将以以下分阶段 R21/R33 形式进行： R21 阶段：目标 1：定义 DLBCL B 细胞和这些肿瘤中存在的非恶性细胞的激酶组。目标 2：定义这些肿瘤中存在的 FL B 细胞和非恶性细胞的激酶组。目标 3：确定 DLBCL 中与疾病临床参数相关的激酶组改变。 R33 阶段：目标 4：识别 FL 中与疾病临床参数相关的激酶组改变。目标 5：确定失调的激酶是否有助于体内 NHL 生长。