The molecular genetics of F-MuLV-induced erythroleukaemias

grantor: University of TorontoThe maintenance of tissue homeostasis, namely correctly maintaining "normal" cell numbers throughout the lifetime of a multicellular organism, is a complex process that becomes disabled during tumorigenesis. This breakdown of homeostatic mechanisms during cellular transformation involves the accumulation of discrete cellular changes, that often result in the cell's proliferative and spatial autonomy. Confirmation that these discrete changes are genetic in nature represents a quantum leap in our understanding of this disease, that has consequently defined, in large part, the nature of our quarry as cancer biologists. The work described in this thesis has attempted to define the role of several genetic mutations during the multistage progression of F-MuLV-induced erythroleukaemias. Of the genetic changes so far identified, proviral insertional activation of Fli-1 appears to be the primary mutational event. The appearance of clonal Fli-1 rearrangements exactly coincides with the blocked differentiation and enhanced self-renewal of these transformed erythroid progenitor cells. Although p53 mutations do not play an important role in the in vivo progression of F-MuLV induced erythroleukaemias, they do appear to be required for the in vitro immortalization process. The recurrent rearrangement and activation of the Epo gene during the establishment of growth factor-independent cell lines, underscores the importance of the Epo/Epo-R signalling pathway in the survival of these transformed erythroid progenitor cells.Ph.D