): This proposal creates a program of mentored research to assist the candidate to complete the transition to independent investigator by providing special guidance in the study of receptor signaling pathways. The candidate has exhibited a long-standing interest in the mechanisms of B cell neoplasia. Under the mentorship of Dr. Michael Kuehl at the National Cancer Institute, he received extensive training in molecular biology and B cell differentiation. He has made important and independent contributions to the field, and is at the juncture of establishing a career as an independent investigator studying the molecular pathogenesis of plasma cell neoplasms. Significantly, he has identified the dysregulation of fibroblast growth factor receptor 3 by chromosome translocation to the immunoglobin heavy chain (IgH) locus in multiple myeloma. Dr. Kendall Smith, a well-established and productive investigator with extensive experience studying IL-2 receptor signaling in lymphocytes, will provide the candidate with supervision and advice in cell biology and receptor signaling, so that the candidate's research can effectively extend to a study of the biological implications of his genetic discoveries. Dr. Barbara Hempstead, an expert on trk receptor tyrosine kinase signaling, will provide special assistance in studying FGFR3 signaling and will serve as a role model. The candidate's immediate career goals are to establish a successful laboratory effort, initially focused on identifying and studying the genes dysregulated by IgH translocation in multiple myeloma. His long-term career goals are to create a comprehensive clinical and laboratory program devoted to the treatment and study of plasma cell neoplasms, and to translate the discoveries in the pathogenesis of myeloma into improved prevention and treatment strategies. The candidate recently identified previously unrecognized, frequent and promiscuous translocations to the IgH locus in multiple myeloma. The research plan has two specific aims: 1) to identify the genes dysregulated by IgH translocation in multiple myeloma, and 2) to study the mechanism by which these genes contribute to malignant transformation and progression. In lymphomas, the identification and characterization of genes dysregulated by IgH translocation (c-myc, cyclin D1, bcl-2) have markedly enhanced the understanding of the pathways involved in cell proliferation, differentiation and death relevant to all tumor and cell types, and the applicant expects that the same will hold true for the genes identified in multiple myeloma.
