UC Davis researchers shed new light on how chemotherapy-induced leukemia develops

Potentially fatal side-effect may be preventable, new study suggests

Topoisomerase II inhibitors are among the most successful chemotherapy drugs used to treat human cancer. But a small percentage of patients treated with these agents recover from their initial malignancy only to develop a second cancer, leukemia.
Researchers at UC Davis Cancer Center have shed new light on this poorly understood process. In a study to be published in the Nov. 22 issue of the journal Leukemia, the researchers report that topoisomerase II inhibitors do not directly cause leukemia — and suggest that it may be possible to prevent therapy-induced leukemia. (The study was posted online in the journal on Sept. 29.)

“There are two competing theories of how these therapy-induced leukemias arise,” said Andrew Vaughan, a radiation biologist at UC Davis Cancer Center and senior author of the new study. “One is that the topoisomerase II inhibitor drugs, in combination with the topoisomerase II enzyme they target, induce random genetic changes that lead to leukemia onset. The other is that another, potentially correctable process is at work.”

In the study, Vaughan and his colleagues at Loyola University and the Sacramento Veterans Administration Hospital linked what appears to be the earliest molecular event involved in the development of therapy-induced leukemia, the rearrangement of the MLL gene (a gene involved in leukemia), to factors that activate apoptosis, or programmed cell death.

“This rearrangement appears to be independent of the topoisomerase II enzyme,” Vaughan said. “This suggests that another process, such as apoptosis itself, is involved.”

Topoisomerase II inhibitors work by goading cancerous cells into apoptosis. Vaughan suggests that therapy-induced leukemia may occur when some cancer cells fail to complete apoptosis and instead survive in a mutated form that contains the leukemia-inducing MLL gene.

“The good news is that apoptosis is a well-understood and potentially correctable process,” Vaughan said. “Through genetic or pharmacologic means, we may be able to manipulate the cells that survive chemotherapy to complete apoptosis and die — averting the development of leukemia.”