Coleman Lindsley, MD, PhD | Aplastic Anemia & MDS International Foundation Return to top.

Coleman Lindsley, MD, PhD

Impact of telomere length and telomerase gene mutations on allogeneic stem cell transplantation outcomes in myelodysplastic syndromes
Original Research Center: 
Dana Farber Cancer Institute
Pubmed Author Name: 
Lindsley RC

Myelodysplastic syndrome (MDS) is a diverse group of bone marrow diseases, unified by poor blood counts and a propensity for development of acute leukemia. MDS is most often diagnosed in older adults, arising as part of aging and without a toxic exposure or predisposing medical condition. In rare cases, however, MDS develops as a complication of an inherited bone marrow disease, such as dyskeratosis congenita, which causes a defect in telomere maintenance and have an increased risk of developing MDS and leukemia. Telomeres are caps that protects the ends of chromosomes from deterioration, and are important for preventing premature cellular aging. In preliminary studies in a large international cohort of MDS patients, we found that an unexpectedly high number of MDS patients have inherited abnormalities in genes important for telomere maintenance, that most of these patients were not known to have dyskeratosis congenita, and that their survival after bone marrow transplantation was poor, resulting from an elevated risk of transplant-related complications. Moreover, 3% of patients have rare inherited changes in telomerase genes that are of unknown clinical significance. Our results suggest that inherited variability in telomerase function is important for risk of MDS development, but that current methods for accurately identifying the patients with most risk are inadequate. Therefore, we propose to measure telomere length in the blood cells of MDS patients and correlate with clinical and genetic information. Based on this information, we will perform laboratory analysis of candidate mutations to determine their effect on telomerase function. To complete these studies, we already have samples from more than 1500 MDS patients, collected over 10 years from 130 different institutions, with complete genetic and clinical annotation. In the future, the results of this study may inform the prognosis and choice of treatment for MDS patients, and drive development of better therapies.

2017
First Year Report: 

Myelodysplastic syndrome (MDS) is a diverse group of bone marrow diseases, unified by poor blood counts and a propensity for development of acute leukemia. MDS is most often diagnosed in older adults, arising as part of aging and without a toxic exposure or predisposing medical condition. In rare cases, however, MDS develops as a complication of an inherited bone marrow disease, such as dyskeratosis congenita, which causes a defect in telomere maintenance and have an increased risk of developing MDS and leukemia. Telomeres are caps that protects the ends of chromosomes from deterioration, and are important for preventing premature cellular aging.
In the first year of the award, we have measured the length of telomeres in the entire cohort of 1514 MDS patients across all ages and completed our genetic analysis of telomerase complex genes. We are currently correlating these results with clinical information to determine whether telomere length influences outcomes in MDS patients receiving allogeneic transplantation. Additionally, we have identified a number of patients that have rare inherited changes in telomerase genes that are of unknown clinical or biological significance. We are testing the impact of these rare changes on telomerase function in the laboratory in order to determine whether they may be involved in the process of MDS development in these patients.

Final Report: 

Myelodysplastic syndrome (MDS) is a diverse group of bone marrow diseases, unified by poor blood counts and a propensity for development of acute leukemia. MDS is most often diagnosed in older adults, arising as part of aging and without a toxic exposure or predisposing medical condition. In rare cases, however, MDS develops as a complication of an inherited bone marrow disease, such as dyskeratosis congenita, which causes a defect
in telomere maintenance and have an increased risk of developing MDS and leukemia. Telomeres are caps that protects the ends of chromosomes from deterioration, and are important for preventing premature cellular aging.
During the period of award, we measured the length of telomeres in the entire cohort of 1514 MDS patients across all ages and determined how telomere length influences outcomes in MDS patients receiving allogeneic transplantation. We found that shorter telomere length was associated with worse survival due to an increased risk of early toxicity, specifically among patients receiving intensive conditioning regimens. We also completed our genetic analysis of telomerase complex genes. We found that approximately 3% of MDS patients had mutations in these genes, and that mutations were associated with short telomere length, younger age of diagnosis, and worse survival due to increased
transplant-related toxicity. In the laboratory, we tested 20 different mutations, confirming that most caused inactivation of telomerase function.

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