Myelodysplastic syndromes (MDS) are a heterogeneous set of clonal disorders characterized by ineffective blood cell development. These diseases are driven by many complex genetic and non-genetic changes. Recent findings have uncovered that alterations in the bone marrow microenvironment contribute to the disease. In our preliminary data, we have found that the beta-catenin pathway is activated in the bone marrow and in the blood of patients with MDS and this predicts a poor clinical outcome. We demonstrate that changes in the stroma increase beta-catenin in the MDS cells and can be targeted by new drugs. We will utilize mouse models, cells lines and patient samples to understand how the bone marrow environment is altered in patients and utilize newly developed beta-catenin pathway inhibitors to reverse the disease.