Often likened to the plastic tips on shoelaces that prevent their unraveling, telomeres are molecular structures that cap the ends of chromosomes in cells and protect their DNA from damage. Chromosomes are thread-like structures that contain and organize the genes and other DNA in cells.
Telomeres play a direct role in a person’s biological clock of aging. Telomeres shorten whenever a cell divides, decreasing protection of the chromosomes. After a certain number of divisions, one of two things happens:
- The chromosomes become damaged and genetically unstable to the point that the cells can’t divide anymore — a state called senescence.
- The cells trigger a self-destruct program, known as apoptosis, ending the life of the cell.
An enzyme called telomerase helps manage telomere length. It is active in stem cells, keeping them alive and resilient so they can continually replenish organs and blood. Telomerase is silenced in most normal cells created by stem cells.
However, telomerase is also active in an estimated 85% to 95% of human cancer cells. As a result, cancer cells essentially become immortal. For this reason, some have called telomerase the “immortality enzyme.”
“Telomerase is a core driver of cancer, it’s involved in increased risk of developing cancer, and it influences toxicities from treatments for cancer,” says Dana-Farber investigator R. Coleman Lindsley, MD, PhD. “It’s a central process and a big focus of our research at Dana-Farber.”
What research is underway regarding telomerase and cancer?
Telomerase has been seen as an attractive target for cancer therapeutics, but development of telomerase inhibitors has proved challenging. At present, there are no clinically approved strategies to exploit telomerase as a cancer therapy target.
Lindsley’s research focuses on a gene called TERT, which provides instructions for the production of telomerase. Variations in TERT can influence how active telomerase is in cells. Some TERT variants passed down through families result in an inherited higher risk of cancers such as melanoma, a skin cancer, and myelodysplastic syndrome (MDS), a blood cancer.
In research investigating the relationship between inherited TERT mutations and the development of blood cancers, Lindsley’s team examined a registry of patients who received stem cell transplants for MDS. They found that 3 to 4 percent of the patients had inherited mutations affecting telomere maintenance, including 2 to 3 percent with TERT mutations. In addition, those patients tended to develop MDS 5 to 10 years earlier and had shorter telomeres.
Lindsley’s lab is continuing this research to learn more about these mutations and their influence on blood cancer development and outcomes.
What research is underway regarding telomeres and cancer?
Lindsley has found that telomere length in blood cells could influence outcomes for patients with blood cancer who undergo stem cell transplantation. His lab’s research has shown that telomere length is an important factor in both the blood cells of the donor and the recipient of the transplanted cells.
Telomeres in stem cell transplant recipients:
Lindsley studied blood telomere length in a large registry of stem cell transplant recipients being treated for MDS. Recipients with short blood telomeres had a much higher risk of dying from a complication of their transplant, even if they did not relapse.
Short telomeres in the patient’s blood cells could indicate that the patient’s stem cells are generally less resilient, making it harder for the patient to tolerate the transplant. For example, if a transplant recipient experiences toxicities in the gut after a transplant, their gut stem cells won’t be as capable of repairing the organ if they have short telomeres.
In the study, patients with short telomeres who received reduced intensity transplants had better outcomes. The research could lead to increased personalization that includes telomere assessment to guide treatment decisions.
More research is required to develop clinical telomere assessments, which currently are only done in research labs, and validate the approach in clinical trials.
Telomeres in stem cell transplant donors:
Donors of blood stem cells tend to be selected based on their chronological age and how well the cells match with the recipient immunologically. Based on Lindsley’s research, telomere length could add a biological aging dimension to that assessment.
In a study of more than 7,000 patients who received stem cell transplant for MDS, AML, or acute lymphoblastic leukemia (ALL), the team found that donor cells with shorter telomeres were associated with higher levels of mortality for stem cell recipients.
“We currently use chronological age as a donor screening tool,” says Lindsley, who partnered with the NMDP on this study as part of an effort to improve precision in donor selection. “But we’re investigating the possibility of adding a dimension to that based on telomere length.”
More research is required before this approach is implemented in the clinic.