2. Academic Validation
  3. Polθ activity modulates sensitivity to standard therapies in DNMT3A-deficient leukemia

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

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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