The Kinomes of Non-Hodgkin Lymphoma

描述（由申请人提供）：基因图谱技术使肿瘤细胞的转录组和蛋白质组分析成为可能。事实上，对非霍奇金淋巴瘤（NHL）转录组的大量平行分析已经揭示了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。这一信息为促进NHL患者生存和增殖的分子机制提供了有用的见解。然而，一个同样重要的目标是确定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反应中发挥重要作用。确定这些信号通路在这些肿瘤中的NHL B细胞和非恶性细胞中是如何改变的，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。我们正在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。这项建议将分两个阶段进行。R21期将包括两个目标，将验证PepChip技术可以识别原发性DLBCL （Aim 1）和FL （Aim 2）分离株的kinome改变。R33期将包括两个目标，将确定DLBCL （Aim 3）和FL （Aim 4）中与临床参数相关的kinome改变。在Aim 5中，我们将利用FL和DLBCL的体内模型来确定失调激酶特异性抑制剂是否能抑制免疫缺陷小鼠NHL肿瘤的生长。该研究将在以下R21/R33阶段进行：R21阶段：目的1：确定这些肿瘤中存在的DLBCL B细胞和非恶性细胞的激酶。目的2：明确这些肿瘤中FL B细胞和非恶性细胞的激酶。目的3：确定DLBCL中与疾病临床参数相关的kinome改变。R33期：目的4：确定FL中与疾病临床参数相关的kinome改变。目的5：确定不受调节的激酶是否有助于体内NHL的生长。

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.