Researchers in City of Hope’s Division of Leukemia and Stem Cell Biology may have found a clue to why blood stem cell transplants can lead to other cancers. The work appeared in the Feb. 10 issue of the Journal of Clinical Oncology.

Ravi Bhatia, back, and Sujata Chakraborty explore why transplants may spur other cancers. (Photo by Darrin S. Joy)

As many as a quarter of all lymphoma patients who undergo this type of transplant later develop myelodysplasia or AML — short for acute myelogenous leukemia — within two years. Patients with myelodysplasia have difficulty producing healthy blood cells. The disease often leads to AML.

Bhatia’s team studied the chromosomes within blood cells taken from newly transplanted patients. Specifically, they measured the chromosomes’ telomeres.

Telomeres are small stretches of repeating DNA at the tips of chromosomes. They act like protective caps that keep the chromosomal tips in tact, similar to how the plastic ends of shoelaces prevent the laces from unraveling. As a person ages and the body’s cells divide over a lifetime, telomeres naturally become shorter. This eventually prevents cells from dividing any further and replacing and regenerating tissues.

However, Bhatia’s team found telomere length underwent drastic, unexpected changes shortly after transplantation.

They studied 287 lymphoma patients who had undergone autologous transplants and found that, among patients who developed myelodysplasia or AML, the telomeres appeared to get longer early after transplantation and then rapidly shortened prior to development of myelodysplasia.

“We believe the accelerated shortening of telomeres makes the chromosomes highly unstable,” said Bhatia. That instability might trigger cells to become cancerous.

According to Sujata Chakraborty, Ph.D., research fellow in Bhatia’s lab and lead author on the study, changes in telomere length likely result from defects in telomere maintenance in stem cells trying to reconstitute the body’s marrow after transplantation.

“Within 100 days after transplant, the environment favors cells that can reconstitute the blood quickly,” she explained. Those cells tend to have longer telomeres.

But the stress of further cell division associated with bone marrow regeneration and continued production of blood cells might cause the rapid decrease in telomere length seen in blood cells later.

“This telomere shortening then leads the stem cells to become unstable and cancerous, resulting in myelodysplasia and eventually AML,” she said.

The researchers are continuing their studies to clarify the molecular mechanisms involved. They hope the data will eventually lead to new or improved techniques that reduce the likelihood for transplant-related secondary cancers in patients undergoing autologous transplants.

Others in the study included these City of Hope investigators: Liang Li, Ph.D., senior research fellow in the Division of Leukemia and Stem Cell Biology; Karen L. Chang, M.D., chief of clinical pathology; Stephen J. Forman, M.D., the Francis and Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation; and, from the Department of Populations Sciences, Can-Lan Sun, M.D., Ph.D., assistant research scientist, Liton Francisco, clinical research coordinator, Melanie Sabado, clinical research assistant, and Smita Bhatia, M.D., M.P.H., department chair.