Hematopoietic stem cells (HSCs) are responsible for the lifelong regeneration of the blood and bone marrow. During the lifetime of an individual, genetic mutations can occur in HSCs that slightly alter their properties, potentially leading to diseases of excessive or deficient production of blood cells. When myeloid cells are chronically affected, these conditions fall into two main categories called myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). These disorders are the most common blood cancers in adults with ~20,000 new cases diagnosed each year in the United States. While these diseases themselves present significant problems such as excessive bleeding and more susceptibility to infections, in a significant number of these patients the disease transforms to a leukemia that is much more difficult to treat and rapidly proves fatal (typically about five months). It is important to identify the genetic processes associated with progression of MDS and MPN to leukemia to improve treatment of these patients. I believe we have identified a new pathway that facilitates this process by identifying a gene that is genetically mutated specifically in the leukemia phase of the disease, but not the preceding MPN phase. The goals of this work are to develop new models to understand these processes, and to identify factors to improve the treatment outcomes of such patients. As there are no effective therapies for these patients that progress to leukemia, any findings that improve the diagnosis and treatment of these patients would represent a significant advance in this field.