Our research focuses on the signals that control stem cell self-renewal and how these signals are hijacked in cancer. Using a series of genetic models, we have studied how classic developmental signaling pathways such as Wnt, Hedgehog and Notch play key roles in hematopoietic stem cell growth and regeneration and are dysregulated during leukemia development. In addition, using real-time imaging strategies we have found that hematopoietic stem cells have the capacity to undergo both symmetric and asymmetric division, and that shifts in the balance between these modes of division are subverted by oncogenes. Further, regulators of this process, including the cell fate determinant Musashi, are critical players in driving progression of solid and liquid cancers and could serve as targets for diagnostics and therapy. Ongoing work is focused on understanding the mechanisms that drive therapy resistance after drug delivery, as well as developing high resolution in vivo imaging approaches to map normal stem cell behavior and interactions within living animals, and to define how these change during cancer formation.