Peptide Blocks DNA Breaks That Cause Leukemia After Cancer Treatment

A small protein fragment can block the DNA breaks that sometimes lead to leukemia years after cancer treatment, according to a study published in Nature Communications. The finding points toward a possible way to prevent one of the most serious long-term consequences of chemotherapy and radiotherapy.

As cancer survival rates have improved, more patients are living long enough to develop what are called secondary leukemias, cancers triggered not by the original disease but by the treatment itself. Chemotherapy and radiation can cause cellular stress that breaks DNA in specific parts of the genome. When the body's own repair machinery fixes those breaks incorrectly, the resulting genetic rearrangements can set leukemia in motion.

According to the report by Phys.org, one particular stretch of DNA is especially vulnerable. It sits inside a gene called MLL, also known as KMT2A, and spans only about 400 base pairs. Professor Lisa Wiesmüller, who heads the Gynecological Oncology Section at Ulm University Hospital, has studied this segment for many years. "A small region of the so-called MLL or KMT2A gene is particularly susceptible to DNA breaks. It is known that these lesions occur frequently in this region in infant leukemias as well as in secondary leukemias," she explained.

Wiesmüller's group had already identified the responsible enzyme back in 2015. It is called endonuclease G, or EndoG, and it cuts DNA the way scissors cut paper. The new study goes further by identifying something that can stop it. Researchers found that a section of a DNA repair protein called Ku80 acts as a natural inhibitor of EndoG inside human cells. It is the first time such an antagonist has been identified in human biology.

The discovery came from an unlikely starting point. A member of Wiesmüller's team noticed a passing reference buried in the discussion section of a specialist article. It mentioned that a region of Ku80 resembles a natural inhibitor that blocks EndoG in the fruit fly Drosophila. "It was immediately clear to us that this was highly interesting and that we had to investigate it," Wiesmüller said.

The researchers confirmed that Ku80 does in fact interact directly with EndoG. From there, they developed synthetic peptides designed to copy the inhibitory effect of the relevant Ku80 region. In cell models, one of those peptides significantly reduced the DNA changes associated with leukemia development.

The work involved collaboration between Wiesmüller's group, Professor J. Christof M. Gebhardt from the Institute of Experimental Physics at Ulm University, and Elsa Sanchez-Garcia from TU Dortmund University. The study was published in Nature Communications.

The research does not yet represent a treatment ready for patients. The experiments were conducted in cell models, not in humans. But identifying both the mechanism behind these DNA breaks and a natural molecule capable of blocking them gives researchers a defined target to work with as they explore prevention strategies for treatment-induced leukemia.