? 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. ? ?
