During the course of the award period, we have made substantial progress toward our objectives of discovering novel and important mechanisms that regulate hematopoietic stem cell fate and have also developed candidate therapeutics targeting hematopoietic stem cells that are moving forward in clinical development. We have published 22 high impact papers during the funding period, including publications in Nature Medicine, Cell Stem Cell, Nature Communications, Journal of Clinical Investigation, and Cell Reports. During this time, we have discovered several novel mechanisms that regulate hematopoietic stem cell regeneration, including the Dickkopf-1/epidermal growth factor signaling pathway, the protein tyrosine phosphatase – sigma signaling pathway and the semaphorin 3A – NRP1 signaling pathway. We have also discovered a critical pathway, the cell-autonomous PTN signaling pathway, through which chronic myeloid leukemia stem cells regulate their survival and disease progression in vivo. Furthermore, we have developed small molecule therapeutic lead compounds targeting protein tyrosine phosphatase – sigma for human hematopoietic stem cell regeneration in patients and are developing lead monoclonal anti-human PTN antibodies for the treatment of patients with chronic myeloid leukemia, in combination with tyrosine kinase inhibitors. Overall, we have made enormous progress within 5 years and our work has provided the foundation for numerous stem cell therapeutics to be developed for years to come.