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（由申请人提供）：基因分析技术已实现对肿瘤细胞转录组和蛋白质组的分析。实际上，对非霍奇金淋巴瘤（NHL）转录组的大规模平行分析显示，NHL的主要亚型，弥漫性大B细胞淋巴瘤（DLBCL）和卵泡淋巴瘤（FL）的主要亚型具有离散的基因谱特征。该信息为分子机制提供了有用的见解，从而促进了NHL的生存和增殖。但是，同样重要的目标是定义那些参与活跃于淋巴瘤细胞和非恶性细胞的信号通路的蛋白质，这些蛋白质会浸润这些肿瘤。其他蛋白质上磷酸化酪氨酸，丝氨酸和苏氨酸残基的酶在控制细胞周期进入，生存，血管生成和免疫反应的信号级联中起主要作用。定义这些信号通路如何改变这些肿瘤中的NHL B细胞和非恶性细胞将提供关键信息，以了解淋巴瘤如何在肿瘤部位生存，增殖和与其他细胞相互作用。我们将纯化的肿瘤细胞应用于一种新型阵列策略，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。该提议将分为两个阶段。 R21阶段将由两个目标组成，这些目标将验证Pepchip技术可以识别主要DLBCL（AIM 1）和FL（AIM 2）分离株中的Kinome改变。 R33阶段将由两个目标组成，这些目标将定义与临床参数相关的DLBCL（AIM 3）和FL（AIM 4）中的Kinome改变。在AIM 5中，我们将利用FL和DLBCL的体内模型来确定针对失控激酶的抑制剂是否抑制免疫缺陷小鼠NHL肿瘤的生长。这项研究将以以下分阶段R21/R33格式进行：R21阶段：AIM 1：定义这些肿瘤中存在的DLBCL B细胞和非恶性细胞的Kinome。 AIM 2：定义这些肿瘤中存在的FL B细胞和非恶性细胞的Kinome。 AIM 3：确定DLBCL中的活化组改变与疾病的临床参数相关。 R33阶段：目标4：识别FL中的Kinome改变与疾病的临床参数相关。 AIM 5：确定失控的激酶是否有助于体内NHL的生长。