The importance of the bone marrow environment in regulating normal hematopoiesis is well established, but its contribution to myeloid leukemogenesis remains largely undefined. Cell-cell and cell-extracellular matrix interactions within the bone marrow are critical control events that constitute potential targets for leukemogenesis. The proposed aims are to explore the molecular mechanisms of stromal signalling in hematopoietic cells and the disorders of these mechanisms in acute myeloid leukemia. The expression of aminopeptidase N/CD13 (APN) on the myeloid cell surface is regulated by stromal cell contact, with the involvement of myb/ets factors. APN expression is also uniquely reduced in leukemias with the t(8;21) translocation--a lesion that generates a chimeric regulatory protein AML-ETO. The Investigator proposes that AML-ETO interferes with normal AML-1 signalling to the myb/ets-APN pathway, thus blocking APN expression. The two specific aims are designed to define the specific signals generated by the interaction of myeloid cells and stromal cells, focussing on the myb ets pathway, and to assess the impact of AML-ETO on the myb ets-APN pathway.
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