Poorly differentiated aggressive myeloid diseases are often resistant to standard therapy and associated with significantly poor survival in both children and adults. There is thus a significant need for a better understanding of the mechanisms that drive disease progression and for finding novel therapeutic targets. While intrinsic signals that drive myeloid cancer progression are well described, the role of interactions with the surrounding microenvironment on leukemic growth remain poorly understood. Our primary goal is to define the role of cancer stem cell interactions with their bone marrow niche in disease progression. To address these questions, we use genetic mouse models of human disease and primary human patient samples, single cell technologies, as well as metabolomic approaches. In the long term, these studies will not only add to our understanding of the tumor microenvironment in the development and progression of hematological malignancies, but may also contribute to the design of novel therapies.