Proteomic biomarkers for lymphoma

描述（由申请人提供）： 这项研究的目的是开发新的淋巴恶性肿瘤的蛋白质组学特征。静息或增殖的正常B细胞和增殖的恶性B细胞的全基因组转录谱鉴定了基因表达的两个主轴：一组基因在静息和增殖的正常细胞之间显著差异表达（“增殖特征”），另一组基因沿沿着与正常增殖无关的正交轴差异表达（“癌症特征”）。淋巴瘤的转录特征为所提出的工作建立了基础和理由;淋巴恶性肿瘤的蛋白质组特征是必需的，部分原因是基于信使RNA的信号不是基于蛋白质的信号的完美代理。初步研究确立了我们提取小鼠或人来源的淋巴组织样品进行2D PAGE分离，然后进行质谱分析（胰蛋白酶肽的MALDI和LC-MS/MS）和淋巴恶性肿瘤潜在生物标志物的蛋白质组学鉴定的能力：“恶性肿瘤蛋白质组”。我们的初步结果支持一个中心假设：休息和促分裂激活，正常淋巴细胞提供了一个框架来解释恶性增殖。拟议的研究将在一个具体目标下进行，有两个次级目标。子目标1：定义取自小鼠脾脏的静息、活化和恶性转基因B细胞的蛋白质组学2D参考图谱。次级目标2：采用类似的方法研究来自诊断为淋巴恶性肿瘤的患者的人类原发组织的恶性特异性特征。我们期望了解一组相对简单的蛋白质生物标志物定义增殖的恶性B细胞，不同于增殖的正常B细胞。根据我们的研究结果，我们预计，正常的静息淋巴亚群和相同的亚群在体外促有丝分裂激活后的边界条件提供了一个有用的启发，解释诱导的B细胞蛋白是独特的恶性状态。这种方法大大简化了淋巴恶性肿瘤的蛋白质组生物标志物的发现。启发式应该是适应性和可扩展到广泛的人类血液恶性肿瘤，包括骨髓性白血病。

DESCRIPTION (provided by applicant): The goal of the proposed research is to develop new proteomic signatures of lymphoid malignancy. Genome-wide transcriptional profiling of resting or proliferating normal B cells and proliferating malignant B cells identified two major axes of gene expression: one group of genes significantly differentially expressed between resting and proliferating normal cells (a "proliferation signature", and another group of genes differentially expressed along an orthogonal axis unrelated to normal proliferation (a "cancer signature"). Transcriptional signatures of lymphomas establish a basis and justification for the proposed work; proteomic signatures of lymphoid malignancy are required in part because messenger RNA-based signals are not a perfect proxy for protein-based signals. Preliminary studies establish our ability to perform extraction of lymphoid tissue samples of murine or human origin, for 2D PAGE separation, followed by mass spectrometry (MALDI and LC-MS/MS of tryptic peptides) and proteomic identification of potential biomarkers for lymphoid malignancy: a "malignancy proteome". Our preliminary results support a central hypothesis: resting and mitogenically activated, normal lymphoid cells provide a framework to interpret malignant proliferation. The proposed research will be conducted under a single Specific Aim, with two subordinate sub-Aims. Sub-Aim 1: Define proteomic 2D reference maps for resting, activated and malignant transgenic B cells taken from mouse spleen. Sub-Aim 2: Employ similar methods to investigate the malignancy-specific signature of human primary tissue from patients diagnosed with lymphoid malignancy. We expect to learn that a relatively simple set of protein biomarkers defines proliferating malignant B cells, distinct from proliferating normal B cells. Based on our results so far, we expect that the boundary conditions of normal resting lymphoid subpopulations and the same subpopulations after in vitro mitogenic activation provide a useful heuristic to interpret the induction of B cell proteins that are unique to the malignant state. This approach greatly simplifies proteomic biomarker discovery for lymphoid malignancy. The heuristic should be adaptable and extendable to a wide spectrum of human hematologic malignancies, including myeloid leukemias.