Biomarkers for lymphoma in a new transgenic mouse model

描述(由申请人提供)： 提出了筛选B细胞淋巴瘤模型分子特征的生物学和统计学论据。在他们的B细胞谱系中结构性地表达一种名为BRD2的新的癌基因的转基因小鼠，我们已经在功能上将其与人类血液系统恶性肿瘤联系在一起，它们零星地以每年10%的速度患上淋巴瘤。给这些小鼠接种一种表达致癌ras的两性逆转录病毒，可以将B细胞淋巴瘤的发生时间加速到四周。这个模型系统有可能识别新的、早期的、恶性前病变的淋巴瘤标志物。人类癌症模型并不具有这些优势，因为个体差异往往使解释变得困难。此外，昂贵的家族基因研究往往是获得系统数据的唯一途径，而人类癌症的发展需要多年的时间。我们进行了全基因组微阵列实验，以检测该B细胞淋巴瘤中基因表达模式的变化，并得出初步结论，它具有与人类大B细胞淋巴瘤非常相似的分子特征，与初步组织学一致。该特征与其他类型的B细胞恶性肿瘤或体外转化的B细胞特征不同，这表明所获得的数据确实将与现有的淋巴瘤特征数据库相媲美，并可能在寻找人类癌症的新生物标记物方面具有临床意义。应用程序要求提供资金进行必要的重复，以便从数据集中得出可靠的结论并获得有关肿瘤进展的数据。这种控制良好的方法将允许及早发现具有统计学意义的、癌前B细胞分子特征的变化，这将为人类淋巴肿大和风险评估提供新的潜在标记物。

DESCRIPTION (provided by applicant): Biological and statistical arguments are presented for a screen for the molecular signature of a B cell lymphoma model. Transgenic mice that constitutively express in their B cell lineage a newly characterized oncogene called BRD2, which we have functionally linked to human hematologic malignancy, sporadically develop lymphoma at an annual rate of 10 percent. Inoculation of these mice with an amphotropic retrovirus that expresses oncogenic ras accelerates the time to B cell lymphoma to four weeks. This model system has the potential to identify new, early, pre-malignant markers of lymphoma. Human models of cancer do not share these advantages, because individual variation often makes interpretation difficult. Furthermore, expensive family genetic studies are often the only way to acquire systematic data, and development of cancer in humans requires many years. We performed a genome-wide microarray experiment to detect altered patterns of gene expression in this B cell lymphoma and came to the preliminary conclusion that it possesses a molecular signature that closely resembles human large-B-cell lymphoma, in agreement with preliminary histology, as expected. The signature does not resemble other types of B cell malignancy or in vitro transformed B cell signatures, suggesting that the data obtained will indeed be comparable to existing databases of lymphoma signatures and could have clinical relevance in the search for new biomarkers for human cancers. The Application justifies a request for funds to perform the replicates necessary to draw reliable conclusions from the datasets and to obtain data on tumor progression. This well-controlled approach will permit the early detection of statistically significant, pre-malignant changes in the molecular signature of B cells, which will provide new potential markers for human lymphomagenesis and risk assessment.