CONTROL OF THE HEMATOPOIETIC DEVELOPMENTAL PROGRAM

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Hematopoietic cells are derived from a limited number of precursor or stem cells which have the properties of self-renewal and maturation. Self-renewal provides for maintenance of precursor cell pool, while maturation ultimately results in production of mature, terminally differentiated cells. During the maturation/terminal differentiation process, the developmental program is established and executed. The purpose of our studies is to determine the mechanisms by which hematopoietic cells control the processes of maturation and terminal differentiation. We will investigate these processes by two approaches. First, we will attempts to identify and characterize general factors which allow the cell to undergo terminal differentiation. To accomplish this goal, we will extend our current observations which indicate that c-myc may have a general effect on the expression of specific genes in highly specialized cells. We will perform deletional and mutational analysis on genes which we have determined are repressed by c-myc expression to find the cis- acting elements responsible for the effect. We will then utilize in vitro transcriptional analysis to determine which trans acting factors are responsible for the effect. We will use information derived from these studies to determine the possible role of this effect on genes expressed in hematopoietic cells. Secondly, we will identify specific factors which allow the expression of specific erythroid genes and will determine how those factors are controlled. We will focus these efforts on factors which affect the expression and regulation of human globin genes. The results of these studies may provide insight into the mechanisms by which hematopoietic differentiation is regulated and guide the development of new strategies for the treatment of hematopoietic malignancies. Furthermore, these studies may result in the identification of specific factors which can augment the expression of normal and hemoglobin synthesis and hemoglobinopathies.