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Fels and Fox Chase Researchers Highlight Roles of TET2 and DNMT3A Mutations in Personalized Medicine-Guided Synthetic Lethality Against Leukemia

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Tomasz Skorski, MD, PhD, DSc, senior author on the study

In a recent study published in Cancer Research, researchers from Fels Cancer Institute for Personalized Medicine at the Lewis Katz School of Medicine at Temple University and Fox Chase Cancer Center identified specific leukemia gene mutations and the mechanisms by which they regulate DNA repair and respond to PARP inhibitors.

Leukemia is a cancer of the bone marrow and blood cells, and its standard treatment usually involves drugs that damage the DNA of both leukemia and normal cells. PARP inhibitors are a type of targeted therapy that are used to induce synthetic lethality in cancers carrying BRCA1/BRCA2 mutations, which are rare in leukemias. They do this by preventing cancer cells from rebuilding their damaged DNA with minimal effect on normal cells. Synthetic lethality refers to cases in which inactivation of two genes results in cell death but inactivation of only one of those genes does not.  

“We designed a strategy so that we can take advantage of the fact that leukemia cells repair the DNA in more effective but different ways from normal cells,” said Tomasz Skorski, MD, PhD, DSc, senior author on the study and director of the Fels Cancer Institute for Personalized Medicine at the Lewis Katz School of Medicine.

“One of the key elements is that we find the specific ways the leukemia cells from particular patients repair the DNA that’s damaged. The leukemia cells in patient A may repair DNA by using different mechanisms than in patient B,” he said. “So it’s important to identify how leukemia cells in both patient A and patient B repair DNA damage and what is different between normal cells in these patients and the leukemia cells.”

Understanding these differences is critical so that researchers can then target these pathways with specific drugs, such as PARP inhibitors, Skorski said. In the study, Skorski and colleagues were able to pinpoint differences between DNA repair pathways in patients with two different mutations.

“The first mutation identified in this paper is in the TET2 gene and the other is in the DNMT3A gene. The product of these genes affect how other genes are expressed including DNA damage repair genes,” said Skorski. “What we have found is that patients with TET2 mutations are extremely sensitive to synthetic lethality triggered by PARP inhibitors. Meanwhile patients with the DNMT3A mutation are resistant. We also identified the mechanisms by which this occurs.”

Skorski said findings from this study may be helpful in developing new personalized therapies tailored for patients with leukemias carrying TET2 mutations. He is currently working on developing a clinical trial to further explore how this information can be applied.

In addition to Fels Cancer Institute for Personalized Medicine and Fox Chase Cancer Center, this study included work done by researchers from multiple institutions. Those institutions include regional groups such as Coriell Institute, Camden, NJ, and national institutions including Washington University School of Medicine, St. Louis, MO; Albert Einstein College of Medicine, Bronx, NY; University of New Mexico, Albuquerque, NM; Memorial Sloan Kettering Cancer Center, New York, NY; Moffitt Malignant Hematology, Pembroke Pines, FL; Mayo Clinic, Rochester, MN.  Several international institutions also contributed to this study including Nencki Institute, Warsaw, Poland; University of Bologna, Bologna, Italy; Medical University of Vienna, Vienna, Austria; Princess Margaret Cancer Center, Toronto, Canada and University of Cambridge, Cambridge, UK.

The study, “TET2 and DNMT3A Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors,” was published in the journal Cancer Research, a journal of the American Association for Cancer Research.