Our major research goal is to understand the mechanisms used to control differentiation and lineage commitment of normal hematopoietic cells, and how these processes are affected by neoplastic transformation. Our efforts focus on the human P210 and P185 bcr-abl oncogenes that are expressed from the philadelphia chromosome (Ph) translocation and their interactions with hematolymphoid progenitor cells. Evidence from the pathogenesis of human Ph+ leukemia suggests that bcr-abl oncogenes can regulate the growth of primitive hematopoietic stem cells that maintain the ability to full differentiate. this raises the possibility that the genes may be used experimentally to stimulate the growth of progenitor populations capable of differentiating along different pathways. such a system would be useful for determining the developmental potential of selected precursor cells and for examining the regulation of hematopoietic differentiation from a developmentally synchronized precursor population. These studies will use retroviral vectors that express bcr-abl to test the interaction of the genes on different hematolymphoid progenitor cells. Specifically we wish to 1. Determine the range and differentiation potential of bcr-abl transformation targets in the thymus, 2. Identify new lymphoid progenitors that can be transformed with the b r-abl viruses and characterize their differentiative potential, and 3. Compare the interaction of different bcr-abl oncogenes and engineered bcr-abl mutants on the differentiation of developmentally synchronized lymphocyte progenitors. This will serve as a model in which to test additional genes that may cooperate with bcr-abl in regulating cell growth vs differentiation. These experiments will contribute to our knowledge of the role of bcr-abl in human leukemias, and provide a way to study the earliest steps in the differentiation of lymphocyte progenitors into mature T and B cells.
