The factors that support the growth and survival of acute myeloid leukemia (AML) are unclear. Filling this gap in knowledge is essential because greater than 12,000 new cases of AML are reported each year, less than 10% of these respond favorably to therapy and approximately 80% of patients eventually relapse despite an initial response to therapy. Our long-term goal is to develop novel treatment strategies that aim to eliminate proliferating leukemia cells and prevent relapse. The control of blood formation in the bone marrow microenvironment occurs through complex interactions involving endosteal and vascular/endothelial niches. Recent data demonstrated that alterations in the activity of these niches may play a role in leukemogenesis. The effects of the endosteal niche are being dissected, but it is clear that the effects of the vascular/endothelial niche in leukemia are still unclear. The objective of this proposal is to determine how activated endothelial cells contribute to the progression and relapse of leukemia and to identify mechanisms that initiate these interactions. The central hypothesis is: endothelial cell activation produces leukemic microenvironments that support the growth, survival and relapse of leukemia. Our preliminary data provide support for this hypothesis. The rationale for the proposed research is that an understanding of this process will result in the development of novel treatment strategies that interfere with this synergistic intercellular relationship. Building on the foundation of our stron preliminary data, our hypothesis will be tested in two specific aims: 1) to define the effects of endothelial cell activation on the growth, survival and relapse of leukemia cells and 2) to define endothelial cell activation activity in response to various therapies and as a predictor of patient outcome.
In Aim 1, we will show that endothelial cell activation is needed to sequester AML cells in a quiescent, chemotherapy resistant state, thus producing the cellular mediators of relapse. We will also demonstrate that AML cells themselves activate endothelial cells suggesting that a 'positive feedback mechanism'exists to propagate the disease. These studies will provide an explanation for the high rates of relapse.
In Aim 2, we will demonstrate that standard chemotherapy agents produce and maintain activated endothelial cells. This finding would suggest that agents commonly used to treat leukemia patients may actually favor relapse, even while concomitantly killing proliferating blast cells. We will also test the effects of blocking endothelial cell activation processes as a way to augment chemotherapy. By completing the proposed studies, we expect to make a significant contribution towards more robust treatment strategies for patients with AML.
Clinical analysis of patients with leukemia has shown increased endothelial cell activity suggesting a role of these cells in the pathogenesis of the disease. This proposal will elucidate how the inflammatory response of endothelial cell activation participates in leukemia progression and relapse. The long-term goals are to use findings to develop novel treatment strategies that aim to treat leukemia while preventing relapse.
