Myelodysplastic syndromes (MDS) are myeloid malignancies most commonly diagnosed at an advanced age. They are considered a spectrum of malignancies that can range from low to high grade and they are classified based on an international prognostic system. This prognostic system separates them into a range from very low risk with survival rates of several years to very high risk with survival rates of less than a year. Therapeutic interventions have focused on targeting higher risk MDS (from intermediate to very high risk), as the benefit of disease-modifying therapies far outweighs the risk of adverse effects from such therapies. Research aimed at developing targets for this disease has described the presence of a subpopulation of leukemia stem cells, which give rise to the disease and are therefore a critical target to eradicate this malignancy. Prior studies have defined metabolic properties of leukemia stem cells, including their reliance in mitochondrial function and oxidative phosphorylation; therefore, targeting oxidative phosphorylation is a potential avenue for eliminating this subpopulation within MDS cells. There are currently very limited therapies aimed at targeting leukemia stem cells, and this is an unmet need in this field. The candidate’s long-term goal will be to develop new therapeutic strategies aimed at targeting this subpopulation. The hypothesis of this study is that signal transducer and activator of transcription 3 (STAT3) regulates mitochondrial function of leukemia stem cells via regulation of several nuclear-encoded genes that are crucial for proper function of the mitochondria, while also translocating to the mitochondria and modulating the function of the electron transport chain. Aim 1 will elucidate whether the IL-6/STAT3 signaling pathway regulates nuclear genes involved in survival of intermediate to very high risk MDS stem cells. Aim 2 will determine whether IL-6/STAT3 signaling regulates the mitochondrial function of higher-risk MDS stem cells. This will be studied by investigating the importance of STAT3 interactions with other proteins in the mitochondria. To determine if either of these roles is essential for survival of leukemia stem cells, Aim 3 will investigate whether targeting IL-6 or STAT3 decreases the engraftment potential of human primary MDS patient samples in immune-deficient mice. Based on these findings, targeting STAT3 and IL-6 will be tested in in vivo models.