Obesity increases both the incidence and mortality of numerous types of cancer. Children and adults who are obese at the time of diagnosis of high-risk acute lymphoblastic leukemia (ALL) have a 50% increased risk of relapse compared to their lean counterparts. Using mouse and tissue culture models, we showed that obesity directly impacts the progression and treatment outcome of ALL. We discovered that adipocytes and ALL cells participate in a two-way communication; ALL cells induce changes in adipocyte morphology and function, and adipocytes in turn release FFA which are used as a fuel for ALL cells. In the present grant, we will further elucidate the mechanisms behind these effects. We will first investigate how ALL cells, in the context of chemotherapy, affect adipocytes, both in culture and in mice and humans. We will then focus on how adipocyte-derived FFA affect ALL cell growth and survival. We have developed novel techniques to perform these studies, including intravital imaging techniques to visualize bone marrow adipocyte and ALL interactions, and single cell lipidomics techniques to elucidate the effects of adipocytes on ALL cell metabolism. These studies will increase our understanding of how leukemia interacts with its microenvironment. They will also improve our understanding of the relationships between ALL and obesity, and they have the potential to change the way we treat cancer in our increasingly overweight population.