The long and the short of telomeres

Telltale enzyme

“Telomerase is detected across all stages and grades in nearly 90 percent of cancers,” DiNardo says. “This suggests that telomerase mutations are generally an early event in cancer progression.”

DiNardo heads an MD Anderson program on hereditary hematological alignancies that includes a group of diseases known as telomere syndromes. People with these syndromes inherit gene mutations involved in telomere maintenance, putting them at higher risk of developing certain cancers. Many also share unique symptoms such as unusual skin and hair discoloration, nail disease and white patches in the mouth.

“Patients with a telomere syndrome known as Dyskeratosis Congenita (DC), have very short telomeres and are at increased risk for bone marrow failure and acute myeloid leukemia (AML) and a group of bone marrow disorders known as myelodysplastic syndromes (MDS). They also have an increased risk of developing solid tumors and pulmonary fibrosis, a respiratory disease in which scars form in lung tissues and lead to serious breathing problems,” DiNardo says.

Those diagnosed with DC at an early age are monitored for their susceptibility to AML or MDS later in life since both diseases tend to strike well into adulthood.

Scientists hope that by measuring telomere length, they may be able to detect cancer or susceptibility to cancer earlier and offer improved treatments based on current telomere-based research.

In the June 2016 issue of the International Journal of Molecular Science, DiNardo wrote about the likelihood for recognizing susceptibility to MDS earlier:

Among sporadic primary MDS in young adults, or those with familial clustering of MDS, an underlying susceptibility to MDS is likely more common than previously considered.

Recognizing patients with potential hereditary syndromes and referring them for genetic evaluation and counseling not only can provide valuable insights for treatment, but also for education, risk assessment, and psychosocial support for patients and their families.”

As many as 10% of people with hematologic malignancies may have an underlying predisposition to cancer that’s linked to elomere syndromes — much higher than previously thought, DiNardo says.

Therapeutic targets

Telomerase is a prime target for cancer therapeutics because it’s found in a majority of tumor types. Several anti-telomerase agents including imetelstat and vaccines are under investigation.

“Telomerase-based immunotherapy is another attractive cancer approach,” DiNardo says. “This is being studied as a possibility because elomerase egradation by cancer cells results in protein fragments and peptides that are exposed on the tumor surface — potential targets for therapy.”

Simona Colla, Ph.D., an assistant professor of Leukemia, is studying how telomeres and telomerase impact cancers like AML and MDS, which fall into a group of disorders linked to defects in telomere maintenance genes, known as telomeropathies.

Colla, along with Derrick Ong, Ph.D., postdoctoral fellow of Cancer Biology, and Ronald DePinho, M.D., professor of Cancer Biology and MD Anderson president, discovered a direct link between telomere dysfunction and MDS. Their findings were published last year in Cancer Cell.

“MDS risks include advancing age, therapy-induced DNA damage, and/or shorter telomeres, but whether telomere erosion directly causes MDS was unknown,” says Colla. “Our study provided evidence that DNA damage caused by telomere loss is linked to this disorder.”

Colla added that their findings were consistent with long-standing observations that poor prognosis in MDS correlates strongly with short telomeres and elevated DNA damage in stem cells. She believes this improved understanding should provide highly specific risk biomarkers for preventing and treating MDS, which today is considered an incurable disease without stem cell transplantation, an option usually not available to most MDS patients due to additional existing illnesses at the time of diagnosis.

The researchers also are studying how stem cells carrying inherited mutations affecting the telomere maintenance pathway can restore telomere function during cancer development.