In this grant application we are interested in addressing the need for the incipient malignant cell to be surrounded by normal cells in order to survive. The development of acute myeloid leukemia from normal bone marrow is a multistep process that takes many years to develop. One major question is how the malignant clone develops from incipient cells that suffer the first mutation. Of particular interest is the role plyed by the surrounding normal cells, both parenchymal and nonparenchymal cells, in supporting this process. We are interested in using the mouse as a model system in which to study this, and have developed a system in which the effects of the surrounding normal cells become apparent. We have made a mouse strain in which all three protein isoforms of EVI1 can be induced to levels comparable to that seen in leukemic cells. Induction of EVI1 expression in all of the bone marrow cells results in bone marrow failure and death within 3-10 days, due to a precipitous drop in mature circulating granulocytes and sepsis. The bone marrow shows a block in myeloid maturation and an accumulation of blast- like cells. In contrast, when EVI1 is induced in just a subset of marrow cells, in a situation where the induced cells are admixed with normal cells, which is closer to the normal physiological way that cancer cells start, the result is very differet: the EVI1-expressing cells emerge in the peripheral blood as atypical granulocytes and the block to differentiation is not seen; the EVI1-expressing cells show a competitive advantage over normal cells, and exhibit a bias towards myeloid differentiation. Continued and sustained EVI1 overexpression by itself does not result in leukemia. In this application, we pursue the role of th normal hematopoietic cells in supporting the incipient malignant cells, in terms of their expansion and maturation. This should provide insight into the early steps in myeloid leukemogenesis, as well as potential novel avenues to treatment.
The early steps in myelodysplastic syndrome (MDS) remain largely unexplored. We have made the observation that incipient MDS clones require normal hematopoietic cells for support. In this application, we wish to explore the nature of this support If it can be characterized and identified, then potentially we can interrupt this supportive signal and eliminate the MDS.
