The deregulation of c-myc expression is a common feature of many natural and experimentally induced neoplasms. The biochemical and subsequent biologic consequences of c-myc activation, however, remain largely unknown. This application proposes experiments utilizing homologous recombination techniques to disrupt deregulated c-myc alleles in avian and human lymphoma cells. Because these cells may require persistant c- myc deregulation for their growth and viability, methods will be developed to produce conditional null mutants in which c-myc expression may be experimentally manipulated in a c-myc null background. These experiments will directly examine the consequences of c-myc deregulation in these tumor cells and determine if c-myc-associated lymphoma cells have a unique requirement for persistant deregulated, or any, c-myc expression. The Max gene is the major binding partner of c-myc, and heterodimerization with Max is required for some (and perhaps all) of c- myc's activities. The Max gene will also be targeted by homologous recombination in avian bursal lymphoma cells to determine if its expression is essential for cell viability, growth, or transformation. Strategies will be developed to produce conditional null and dimerization Max mutants. These mutants will be used to determine if these cells require c-myc/Max heterodimers, as well as to examine possible functional redundancy among the myc family genes. The methods developed during these studies will be applicable to the study of any gene that may be essential for cellular growth and viability. The applicant's interests are in understanding the genetic events underlying neoplastic transformation. Ultimately, he hopes to develop molecular genetics-based cancer treatment strategies, thus combining his scientific training in molecular biology with his clinical training in medical oncology and marrow transplantation. Dr. Groudine is an ideal mentor for this project, for he combines a broad perceptive on cancer with expertise in molecular biology and he is a leader in understanding the regulation of the c-myc gene in normal and malignant cells.
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