Grant: Project Grant

The mechanisms that govern the expansion of human blood stem cells are poorly characterized, with the consequence that bone marrow transplantation remains unavailable to a subset of patients for which graft size is too small, resulting in prolonged engraftment and often lethal complications. We previously identified and developed a small molecule called UM171, which acts as a potent mediator of stem cell expansion with important clinical benefits, as proven in a series of completed and ongoing clinical trials. More recently, we identified a novel protein complex called CRL3KBTBD4 which, under exposure to UM171, is responsible for the degradation of another protein complex called CoREST1 that plays an important role in the "epigenetic" control of key stem cell genes. Epigenetic marks (together referred to as the epigenome) are modifications to DNA and proteins that turn genes on or off. CRL3KBTBD4 activation by UM171 prevents the loss of key epigenetic marks in human blood stem cells that undergo amplification in culture. This work positions the KBTBD4-COREST1 axis as a critical mediator of stem cell amplification. We now propose to study the role of this pathway in human blood stem cells and to understand the downstream epigenetic mechanisms responsible for its unique effector function. This is crucial for the development of improved strategies of stem cell expansion, an important limitation to the success of bone marrow transplantation and gene therapy.