The impact of telomere maintenance on intestinal mucosal injury and regeneration during allogeneic stem cell transplantation for myeloid malignancies.
Christopher Reilly
MDDana-Farber Cancer Institute
Project Term: October 1, 2021 - September 30, 2023
Short telomeres, the protective caps at the ends of DNA, are associated with increased risk of fatal toxicity among stem cell transplant recipients. We will determine 1) the relationship between recipient telomere length and intestinal injury after transplant and 2) how telomere length influences intestinal healing in a transplant mouse model. The goal of this work is to identify transplant patients at increased risk of toxicity and design therapies to improve patient survival.
A blood stem cell transplant from a healthy donor is the only cure for patients with high-risk blood cancers. A central challenge for providers is balancing the curative intent of transplant with the risk of fatal toxicity. Identifying patient variables prior to transplant that accurately predict the likelihood of fatal transplant complications would facilitate interventions to mitigate risk of toxicity and improve patient survival. Telomeres are protective caps at the ends of DNA that shorten as cells divide analogous to a biological clock. Short telomere length is an independent risk factor for fatal treatment toxicity in transplant patients with specific blood cancers. Furthermore, the risk of death is highest among those who have severe intestinal inflammation, suggesting that patients with short telomeres have an impaired capacity to recover from intestinal injury during transplant. Our research will test if patients with short telomeres have an increased risk of fatal transplant toxicity due to an impaired capacity to recover from intestinal injury. This question has never been asked and may identify patients prior to transplant who are at high risk of fatal complications. We will first determine the relationship between telomere length and two validated blood markers of intestinal injury (REG3A and ST2) in patients undergoing a stem cell transplant for a blood cancer. We predict that patients with short telomeres will be more likely to have elevated blood markers of intestinal injury and decreased survival compared to patients with longer telomeres. Next, we will utilize mice with short telomeres to determine how telomere length influences intestinal regeneration following transplant. In this model, severe inflammation from donor immune cells leads to intestinal injury in recipient mice. Compared to healthy mice, we predict that transplanted mice with short telomeres will have decreased survival and impaired intestinal regeneration after injury. We will then determine if the detrimental effect of short telomeres on intestinal recovery from injury can be rescued by several treatments that amplify growth signals to augment intestinal regeneration. Collectively, our results will determine the mechanism by which short telomeres contributes to fatal toxicity in blood cancer patients undergoing transplant and identify therapeutic approaches that may reduce intestinal toxicity and improve patient survival.