REGULATION OF HEMATOPOIESIS BY EPIDERMAL GROWTH FACTOR RECEPTOR

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In humans, amplification of the epidermal growth factor receptor. EGFR gene has been found in sarcomas, squamous cell carcinomas of the head and neck and glioblastomas. In chickens, the oncogene v-ergB is responsible for erythroid leukemia. The v-ergB oncoprotein is homologous to the chicken EGFR, termed c-erbB. The avian system is more amenable than the human cell systems to the genetic and molecular analysis necessary to address mechanistic questions, hence, most mechanistic studies addressing EGFR-mediated oncogenesis have been performed in the avian system. Analysis of two distinct normal chicken erythroid progenitors demonstrated that c-erbB plays a role in erythroid differentiation. Leukemia can be viewed as a block in differentiation, therefore a true understanding of leukemogenesis can only be obtained when we understand the mechanisms that control the normal growth and differentiation of the progenitor cells that become leukemic. In this regard the avian system is unique in that the growth and differentiation of the normal progenitor cells can be studied in vitro and they can also be transformed to a leukemic phenotype. Thus normal and leukemic cells can be compared and the role of various signal transduction pathways in normal erythropoiesis and in the maintenance of the leukemic state determined. Therefore we are using this system to determine the role of c-erbB in normal erythroid cell growth and differentiation and to identify the basic mechanism of transformation by v- ergB. Our specific aims are: 1. To characterize the growth and differentiation of the two erythroid progenitor cells. Determine if they are target cells for transformation by v-erbB, and characterize how leukemic transformation alters their normal growth and behavior. 2. To identify the signal transduction pathways used to control the proliferation and differentiation of normal and transformed erythroid cells. Substrates involved in several signal transduction pathways will be evaluated for their role in the induction of self-renewal by c-erbB and in transformation by v-erbB.