We are excited to share an update on our research project, “Pre-malignant Clonal Evolution in Telomere Biology Disorders,” supported by the Team Telomere Million Dollar Bike Ride Grant. Telomere Biology Disorders (TBD) are genetic diseases that cause critical telomere shortening, frequently leading to bone marrow failure. TBD patients are at an increased risk of developing blood cancers such as myelodysplastic syndrome (MDS) or acute leukemia. Despite recent progress in many aspects of the clinical care of TBD patients, predicting which TBD patients are most at risk of developing blood cancers remains a challenge.
With the grant support from MDBR and Team Telomere, we conducted a study to investigate genetic changes and blood cancer development in TBD patients. We analyzed blood or bone marrow tissue from almost 70 TBD patients enrolled in our patient registries at the University of Pennsylvania and the Children’s Hospital of Philadelphia. Our findings revealed that over 40% of TBD patients had new genetic changes in their blood or bone marrow cells, some of whom developed blood cancers. Notably, the relative frequency of mutations in various genes differed from the common mutations that occur in individuals without TBD and was different from the typical pattern of mutations seen in normal aging and sporadic age-related MDS.
Our results suggest that TBD patients have a distinct pattern of mutation acquisition driven by cellular stress due to telomere shortening. These mutations may enable bone marrow cells of TBD to overcome premature senescence and be protective from severe bone marrow failure; however, this may be at the cost of tolerating genetic damage and may predispose to malignancy. To further our understanding of the significance of these findings, we have secured additional funding, with the support and co-sponsorship from Team Telomere, to investigate gene expression changes in TBD patients and to validate our findings in patient-derived cell culture models. These studies are ongoing, and we look forward to sharing more on the results of this work later this year.
Our study has important implications for understanding the risks associated with new genetic changes in TBD patients and for developing improved surveillance and prevention strategies to lower the risk of blood cancers in TBD in the future. We are grateful to the MDBR grant from Team Telomere for supporting our research, without which our study would not have been possible. We hope that our findings will help inform the development of new therapies and ultimately improve the lives of TBD patients.