While risk for blood cancers varies depending on one’s genetic background, the basis of this variation remains unknown. The overall goal of this project is to understand the mechanisms by which some individuals may be predisposed to blood cancers, as a result of their genetic makeup. Blood cancers such as myelodysplastic syndromes (MDS) are often preceded by a highly prevalent premalignant state called clonal hematopoiesis of indeterminate potential (CHIP). CHIP occurs when blood stem cells acquire mutations and then expand to form unique clones. Recent genetic association studies have identified numerous regions in the human genome that are linked to risk of CHIP clones. This proposal aims to define how genes within these genomic regions interact with acquired CHIP mutations to cause stem cell clones to expand. We are using novel state of the art CRISPR/Cas9 technologies that can screen thousands of mutations to identify critical gene interactions that underlie this disease. In addition, we are also using this technology to understand how normal blood stem cells are transformed into MDS cancer stem cells that stop producing red blood cells which is a serious problem for MDS patients. Knowledge gained from our research could enable the development of new treatments that target CHIP clones and prevent MDS development. This research can also help identify CHIP carriers who are at risk of developing blood cancers later in their life.