Polθ activity modulates sensitivity to standard therapies in DNMT3A-deficient leukemia

  • Cell Rep Med. 2026 Mar 17;7(3):102687. doi: 10.1016/j.xcrm.2026.102687.
Bac Viet Le  1 ,  Umeshkumar Vekariya  1 ,  Monika M Toma  1 ,  Margaret Nieborowska-Skorska  1 ,  Marie-Christine Caron  2 ,  Malgorzata Gozdecka  3 ,  Zayd Haydar  1 ,  Martin Walsh  4 ,  Jayashri Ghosh  1 ,  Elaine Vaughan-Williams  1 ,  Paulina Podszywalow-Bartnicka  5 ,  Anna-Mariya Kukuyan  1 ,  Sylwia Ziolkowska  1 ,  Jessica Atkins  1 ,  Emir Hadzijusufovic  6 ,  Gurushankar Chandramouly  7 ,  Reza Nejati  8 ,  Katarzyna Piwocka  5 ,  Richard Pomerantz  7 ,  George S Vassiliou  3 ,  Brian J P Huntly  3 ,  Peter Valent  9 ,  Mariusz Wasik  8 ,  Alfonso Bellacosa  10 ,  Jean-Yves Masson  2 ,  Gaorav P Gupta  11 ,  Grant A Challen  12 ,  Tomasz Skorski  13
Affiliations
  • 1. Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • 2. CHU de Québec Research Centre (Oncology Division, Hôpital Enfant-Jesus) and Laval University Cancer Research Center, Québec City, QC G1V 4G2, Canada.
  • 3. Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK.
  • 4. Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA, USA; Nuclear Dynamics and Cancer Program, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
  • 5. Laboratory of Cytometry, Nencki Institute of Experimental Biology Polish Academy of Sciences, 02-093 Warsaw, Poland.
  • 6. Department for Companion Animals & Horses, Clinic for Internal Medicine and Infectious Diseases, University of Veterinary Medicine Vienna, Vienna 1210, Austria; Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna 1090, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna 1990, Austria.
  • 7. Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
  • 8. Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
  • 9. Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna 1090, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna 1990, Austria.
  • 10. Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA, USA.
  • 11. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 12. Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
  • 13. Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Electronic address: [email protected].
PMID: 41850232 DOI: 10.1016/j.xcrm.2026.102687
Abstract

Myeloid malignancies carrying somatic DNMT3A mutations (DNMT3Amut) are refractory to standard therapy. DNMT3Amut leukemia cells accumulate toxic DNA double-strand breaks (DSBs) and stalled replication forks, rendering them dependent on DNA damage response (DDR). We report here that DNA Polymerase theta (Polθ), a key element in DSB repair by end-joining (Polθ-mediated end-joining [TMEJ]) and in fork restarting, promotes survival and proliferation of DNMT3Amut leukemia cells. Polθ is overexpressed in DNMT3Amut leukemia cells due to abrogation of PARP1 PARylation-dependent UBE2O E3 ligase-mediated ubiquitination and proteasomal degradation of Polθ. In addition, PARP1-mediated recruitment of the SMARCAD1-MSH2/MSH3 repressive complex to DSBs is diminished in DNMT3Amut leukemia cells, which facilitates association of Polθ with DNA damage. Polθ inhibitors enhance the anti-leukemic effects of standard drugs such as FLT3 kinase inhibitor quizartinib, cytarabine ± doxorubicin, and etoposide in vitro and in mice with DNMT3Amut leukemia. Altogether, Polθ is an attractive target in DNMT3Amut hematological malignancies.

Keywords
DNA polymerase theta; DNMT3A-deficient acute myeloid leukemia; PARP1; TMEJ; replication fork; ubiquitination.
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