The chief objective of our research is to understand the molecular and genetic mechanisms responsible for differentiation, cell growth, and neoplastic transformation. We study the oncogenes, tumor-suppressor genes and signal-transducing proteins in mouse and human experimental tumor systems, including BALB/c mouse plasmacytomas, B-cell lymphomas, and NIH 3T3 cells, among others. These are valuable experimental models, because they can be used to devise more specific therapy and preventive measures for human multiple myeloma, non-Hodgkin's lymphomas, and other human malignancies. BALB/c plasmacytomas, like human Burkitt lymphomas, are characterized by constitutive expression of the proto-oncogene, c-Myc. To determine which additional genetic alterations are required for complete transformation, we are using microarray hybridization studies of global gene expression and array-based Comparative Genomic Hybridization to follow genetic changes and changes in gene expression during progression from pre-malignant to fully malignant plasma cell tumors. We are also using microarray hybridization studies to probe the molecular mechanisms at work in development of plasma cell tumors in mice and the mechanisms whereby certain transgenes and viral oncogenes accelerate this neoplastic process. Global gene expression studies are also underway to determine the physiological changes necessary for these tumors to adapt to growth in tissue culture. It is our hypothesis that such adaptive changes in gene expression that enable tumor cells to grow in the foreign environment of culture vessels might be analogous to those needed for human tumors to grow in alien environments following invasion or metastasis. As an extension of this project, we observed marked differences in gene expression profiles between mouse plasma cell tumors growing in tissue culture and the same tumors growing in intact animals. Our studies that compared global gene expression patterns of B-cell lymphomas in mouse and man with expression patterns of plasma cell neoplasms of murine (plasma cell tumors) and human multiple myeloma showed significant and characteriztic differences not only between B-cell lymphomas and plasma cell neoplasms, but also among different subtypes of human and mouse plasma cell neoplasms. Unsupervised hierarchical cluster analysis of expression patterns of the human and murine plasma cell neoplasms showed a similarity between rapid-appearing mouse plasma cell tumors and MM3 and MM4 multiple myelomas, which had particularly poor clinical prognoses.
