Identifying patients at high risk of fatal treatment toxicity is a central challenge in allogeneic hematopoietic stem cell transplantation (HSCT). More accurate prediction of non-relapse mortality (NRM) risk could inform clinical decisions about timing and approach to HSCT. Short telomere length impairs the cellular response to genotoxic and replicative stress, and limits the regenerative potential of many tissues, including the gastrointestinal mucosa and bone marrow. We recently completed a study that evaluated the relationship between telomere maintenance and transplantation outcomes.
We first evaluated the impact of recipient pre-transplantation telomere length on clinical outcomes in patients with myelodysplastic syndrome (MDS). We found that patients whose blood cells have shorter telomeres have a greater risk of dying after transplantation than patients with longer telomeres, particularly after receiving preparative regimens with high-dose, myeloablative chemotherapy. The adverse effect of shorter telomeres on survival was driven exclusively by a significantly higher risk of NRM, and was independent of recipient comorbidities. The association between telomere length and NRM was most prominent among patients who developed severe acute graft-versus-host disease, suggesting that short telomere length may limit regenerative potential of mucosal tissues after acute injury.
To determine whether unrecognized germline factors explain why some MDS patients have shorter telomeres than others, we sequenced 18 genes known to be involved in telomere maintenance. We found germline mutations in three genes that compose the core telomerase complex — TERT, TERC, and DKC1 — in 49 of 1514 MDS patients (3.2%). Among these, TERT mutations were most common, and were associated with significantly shorter telomeres, an earlier age at MDS diagnosis, and shorter overall survival due to increased NRM. In the laboratory, we performed structural modeling and functional testing to confirm that these novel TERT mutations cause severe impairment of telomere elongation. These results suggest that it may be useful to perform routine germline screening for deleterious telomerase complex mutations in MDS patients.
In order to validate our findings, we are now conducting a prospective observational study of all patients receiving allogeneic HSCT with myeloablative conditioning at DF/BWCC. This study is led by Dr. Chris Reilly, in collaboration with Dr. Corey Cutler, and will focus on evaluating the relationship among telomere length, telomerase mutations, and transplant outcomes. In collaboration with Dr. Nathaniel Treister (Division of Oral Medicine and Dentistry, Brigham and Women's Hospital), we will investigate the impact of telomere length on the severity of mucosal injury after transplantation.
