Biomarkers for lymphoma in a new transgenic mouse model

描述（由申请人提供）： 生物学和统计学参数的筛选的分子签名的B细胞淋巴瘤模型。转基因小鼠在其B细胞谱系中组成性表达一种新特征的癌基因BRD 2，我们已经将其与人类血液恶性肿瘤功能联系起来，以每年10%的速度零星发展淋巴瘤。用表达致癌ras基因的嗜中性逆转录病毒接种这些小鼠，可将B细胞淋巴瘤的时间加速至四周。该模型系统具有识别新的、早期的、恶性淋巴瘤前标志物的潜力。人类癌症模型没有这些优势，因为个体差异往往使解释变得困难。此外，昂贵的家族遗传学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时间。我们进行了全基因组微阵列实验，以检测这种B细胞淋巴瘤中基因表达模式的改变，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，正如预期的那样。该特征不类似于其他类型的B细胞恶性肿瘤或体外转化的B细胞特征，表明所获得的数据确实与淋巴瘤特征的现有数据库相当，并且在寻找人类癌症的新生物标志物中可能具有临床相关性。该申请证明了资金请求的合理性，以执行从数据集得出可靠结论并获得肿瘤进展数据所需的重复实验。这种控制良好的方法将允许早期检测B细胞分子特征中的统计学显著的癌前变化，这将为人类淋巴瘤发生和风险评估提供新的潜在标志物。

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.