Proteomic biomarkers for lymphoma

描述(由申请人提供)： 这项拟议的研究的目标是开发淋巴系统恶性肿瘤的新的蛋白质组特征。对静息或增殖的正常B细胞和增殖的恶性B细胞的全基因组转录图谱确定了两个主要的基因表达轴：一组在静息和增殖的正常细胞之间显著差异表达的基因(“增殖特征”)，以及另一组沿与正常增殖无关的正交轴差异表达的基因(“癌症特征”)。淋巴瘤的转录签名为拟议的工作建立了基础和理由；淋巴恶性肿瘤的蛋白质组签名是必需的，部分原因是基于信使RNA的信号并不是基于蛋白质的信号的完美替代。初步研究确定了我们能够提取小鼠或人类来源的淋巴组织样本，进行2D PAGE分离，然后进行质谱分析(MALDI和胰蛋白酶多肽的LC-MS/MS)和蛋白质组鉴定淋巴系统恶性肿瘤的潜在生物标记物：“恶性蛋白质组”。我们的初步结果支持一个中心假设：静息和有丝分裂激活的正常淋巴样细胞为解释恶性增殖提供了一个框架。拟议的研究将在一个具体目标下进行，有两个次级目标。次目标1：为取自小鼠脾的静息、活化和恶性转基因B细胞建立蛋白质组2D参考图。次目标2：使用类似的方法研究被诊断为淋巴系统恶性肿瘤的患者的人类原始组织的恶性肿瘤特异性特征。我们希望了解到，一组相对简单的蛋白质生物标记物定义了增殖的恶性B细胞，与增殖的正常B细胞不同。基于我们到目前为止的结果，我们期望正常的静息淋巴亚群和体外有丝分裂激活后的相同亚群的边界条件为解释恶性状态特有的B细胞蛋白的诱导提供了有用的启发式方法。这种方法大大简化了淋巴系恶性肿瘤的蛋白质组生物标记物的发现。启发式方法应该适用于和可扩展到包括髓系白血病在内的多种人类血液系统恶性肿瘤。

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.