A potential weakness in a common form of leukemia could lead to new treatments. The discovery, made by researchers at the Lewis Katz School of Medicine at Temple University, shows that leukemia cells with mutations in DNMT3A—a gene often altered in acute myeloid leukemia (AML)—depend on a DNA-repair enzyme known as DNA polymerase theta (Polθ) to survive. Targeting this enzyme could lead to novel ways to fight aggressive leukemia.
The research, published in Cell Reports Medicine, is the first to show that DNMT3A-mutant leukemia cells become highly dependent on Polθ, leaving them vulnerable to attack by selective therapeutic agents.
“DNMT3A mutations are common in AML but leukemia cells carrying these mutations have been difficult to eliminate,” said senior investigator Tomasz Skorski, MD, PhD, DSc, Director of the Fels Cancer Institute for Personalized Medicine and Professor in the Department of Cancer and Cellular Biology at the Lewis Katz School of Medicine and co-leader of the Nuclear Dynamics and Cancer Program at the Fox Chase Cancer Center. “By uncovering the dependency on Polθ, we have identified a new weakness that could be exploited therapeutically.”
DNMT3A mutations occur frequently in myeloid hematological malignancies and are associated with poor responses to treatment and increased risk of relapse. In the new study, Dr. Skorski and colleagues found that leukemia cells carrying these mutations accumulate large amounts of DNA damage, including toxic double-strand breaks and stalled replication forks, points at which the machinery driving DNA replication halts due to obstacles such as strand breaks. To cope with this stress and continue growing, the cells activate repair pathways.
In experiments in DNMT3A-mutant leukemia cells, the researchers found that Polθ, which is a key component of an alternative pathway specialized for repairing DNA double-strand breaks, is central to survival. In particular, the cells express very high levels of Polθ because normal regulatory mechanisms that degrade the enzyme are disrupted, allowing it to accumulate at sites of DNA damage.
“When DNMT3A function is lost, leukemia cells become unusually reliant on this backup pathway,” Dr. Skorski explained. “This led us to the idea of inhibiting Polθ to prevent DNA repair.”
To test that idea, the researchers treated leukemia cells with several experimental Polθ inhibitors. The drugs selectively impaired the survival of DNMT3A-mutant leukemia cells while having much smaller effects on leukemia cells without the mutation and cells obtained from healthy donors. Blocking Polθ caused DNA damage to accumulate and reduced leukemia cell growth in both cell and animal models.
The team also found that Polθ inhibitors could enhance the effectiveness of existing cancer therapies. When combined with chemotherapy drugs such as etoposide or cytarabine—or with targeted treatments like FLT3 inhibitors—the experimental compounds produced much stronger anti-leukemia effects than any single treatment alone. Importantly, the combination strategies worked in leukemia cells taken from patients and injected into animals. In some cases, the dual treatment reduced leukemia cells in the blood of mice to undetectable levels.
“Combining Polθ inhibitors with standard therapies dramatically increased the killing of DNMT3A-mutant leukemia cells,” Dr. Skorski said. “These findings suggest that targeting this pathway could make current treatments more effective.”
The findings could have broad implications because DNMT3A mutations are common in several blood cancers, including AML, myeloproliferative neoplasms, and advanced phases of chronic myeloid leukemia. These mutations are often linked to drug resistance, making new treatment strategies urgently needed.
“Several Polθ inhibitors are already being tested in early-stage clinical trials for other types of cancer,” Dr. Skorski noted. His team’s new work provides a strong rationale for also evaluating these drugs in patients with DNMT3A-mutant leukemias.
Other researchers on the study include: Bac Viet Le, Umeshkumar Vekariya, Monika M. Toma, Margaret Nieborowska-Skorska, Zayd Haydar, Jayashri Ghosh, Elaine Vaughan-Williams, Anna-Mariya Kukuyan, Sylwia Ziolkowska, and Jessica Atkins, Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia; Marie-Christine Caron and Jean-Yves Masson, CHU de Québec Research Centre, Oncology Division, Hôpital Enfant-Jésus, and Laval University Cancer Research Center, Québec City, Canada; Malgorzata Gozdecka, George S. Vassiliou, and Brian J. P. Huntly, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, United Kingdom; Martin Walsh and Alfonso Bellacosa, Cancer Epigenetics Institute and Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia; Paulina Podszywalow-Bartnicka and Katarzyna Piwocka, Laboratory of Cytometry, Nencki Institute of Experimental Biology Polish Academy of Sciences, Warsaw, Poland; Emir Hadzijusufovic and Peter Valent, Department of Internal Medicine I, Division of Hematology and Hemostaseology, and the Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Austria; Gurushankar Chandramouly and Richard Pomerantz, Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia; Reza Nejati and Mariusz Wasik, Department of Pathology, Fox Chase Cancer Center, Philadelphia; Gaorav P. Gupta, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill; and Grant A. Challen, Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis.
The multi-center international research was supported in part by grants from the National Institutes of Health (NIH), the Edward P. Evans Foundation, the Leukemia and Lymphoma Society, and the American Cancer Society.