I. Biology of Multiple Myeloma My laboratory has a long-standing interest in the biology of the bone marrow cancer myeloma. Recently six different genes translocated into the immunoglobulin heavy chain (IgH) switch region during isotype switch recombination in B cells have been implicated in this disease. We have studied one of these genes - fibroblast growth factor receptor 3 - in more detail to determine why ectopic expression would promote plasma cell growth. It appears that overexpression of FGFR3 is oncogenic casuing B cell leukemia in a mouse transplant model and that its B cell regulatory function is mediated by STAT3 and BCL-XL. In ongoing studies we are examining the molecular basis for B cell proliferation induced by FGR3 and by another IgH translocation partner, c-maf. In addition we are examining therapeutic inhibitors of FGR3 in animal models and attempting to correlate FGFR3 or c-maf overexpression with prognosis. In adddition, we have been studying the gene expression profile of multiple myeloma using cDNA library construction, sequencing and microarray techniques. A catalogue of genes expressed in multiple myeloma can be accessed through the Myeloma Gene Index. Using genes from our database we have developed our first generation 4.3K Myeloma Chip. We are currently using this resource in our study of the molecular portrait of myeloma patients. II. Kinome Sequencing Tyrosine kinases are central regulators of signaling pathways that regulate a number of cellular processes such differentiation, cell cycle, apoptosis, transcription, and motility. We have been interested in looking for somatic mutations in tyrosine kinase genes in multiple myeloma. Through a collaboration with The Centre for Applied Genomics (TCGA) at the Hospital for Sick Children, we have been doing high-throughput mutation analysis. We have focused our mutation screening on 90 tyrosine kinase, 43 tyrosine kinase-like and 5 receptor guanylate kinase genes. III. Proteomics Through the partnership of McLaughlin Centre for Molecular Medicine and the Toronto Medical Laboratories, we have begun to utilize ProteinChip (Ciphergen) technology that is based on Surface Enhanced Laser Desorption/Ionization (SELDI) to understand the proteome of multiple myeloma. This technology is vital in identifying biomarkers from clinical samples, and is useful for monitoring the effects of therapeutic interventions in myeloma patients at the protein level.