Improving hematopoietic stem cell transplantation by defining novel regulators of engraftment
Shannon McKinney-Freeman
PhDSt. Jude Children's Research Hospital
Project Term: July 1, 2018 - June 30, 2023
Blood-forming stem cells are routinely transplanted into patients to treat blood cancers. We discovered that multiple members of the GASP (G-protein coupled receptor Associated Sorting Proteins) family inhibit the function of blood-forming stem cells during transplantation. Our goal is to determine exactly how GASP family members inhibit these critical cells in order to inform our efforts to improve the efficiency of blood stem cell transplantation.
Each year in the United States about 3,000 leukemia patients will be treated with a hematopoietic stem cell (HSC) transplant. For many of these patients, HSC transplantation (HSCT) is the only available curative therapy. Stem cells are specialized cells that maintain and repair the tissue in which they reside. HSCs are the stem cell population that maintain blood production in healthy individuals and restore a healthy blood system when transplanted into patients whose own blood system is compromised by leukemia or chemotherapy. Most transplanted HSCs are collected from the blood of donors that have been treated with G-CSF, a drug that coaxes HSC to leave the bone marrow and enter the blood. Unfortunately, G-CSF treatment is a multi-day protocol that comes with high rates of debilitating side-effects, such as fever and bone pain. According to the National Bone Marrow Registry, >50% of potential donors decline donation, many due to fear of these side effects and the inconvenience of current G-CSF treatment protocols. This reality severely limits the donor options of leukemia patients in need of HSCT. Improving the collection of HSC from the blood of donors requires a deep understanding of the mechanisms that regulate how HSCs interact with their bone marrow homes or ‘niches’. Indeed, these same gains in knowledge can also be applied to improve the efficiency of HSC engraftment during transplant, which would allow for reduced pre-transplant conditioning regimens, lowering the long-term risks that plague survivors of leukemia, especially children, such as secondary malignancies, immune dysfunction, growth failure, gonadal dysfunction, and thyroid dysfunction. The major goal of our laboratory is to understand the key mechanisms that control the ability of HSCs to engraft a patient and regenerate the entire blood system. We recently discovered that a family of proteins, known as GPRASP proteins, inhibits the ability of HSC to efficiently replenish the blood system after transplantation. Here, we will determine exactly how these proteins block this critical function. Our hypothesis is that GPRASP proteins degrade critical factors that are required to both attract HSCs to the bone marrow after transplantation and anchor them securely in their niche once they arrive in the bone marrow. This work will illuminate a novel molecular pathway that can be targeted therapeutically, possibly by directly reducing GPRASP function during transplantation, to improve outcomes for leukemia patients in need of HSCT as well as for their donors.