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

Bac Viet Le1, Umeshkumar Vekariya1, Monika M Toma1

  • 1Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.

Cell Reports. Medicine
|March 18, 2026
PubMed

Insights

DNA polymerase theta (Polθ) drives survival in difficult-to-treat DNMT3A-mutated myeloid leukemias. Inhibiting Polθ enhances standard therapies, offering a new therapeutic strategy for these aggressive blood cancers.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • Myeloid malignancies with DNMT3A mutations (DNMT3Amut) show resistance to conventional treatments.
  • DNMT3Amut leukemia cells exhibit increased DNA double-strand breaks (DSBs) and replication stress, creating a dependency on DNA damage response (DDR) pathways.

Purpose of the Study:

  • To investigate the role of DNA polymerase theta (Polθ) in the survival and proliferation of DNMT3Amut leukemia cells.
  • To explore the therapeutic potential of targeting Polθ in DNMT3Amut hematological malignancies.

Main Methods:

  • Analysis of Polθ expression and its regulation in DNMT3Amut leukemia cells.
  • Investigation of Polθ's involvement in DNA repair pathways, specifically Polθ-mediated end-joining (TMEJ).
  • Evaluation of Polθ inhibitors in combination with standard chemotherapies and targeted agents in vitro and in vivo mouse models.

Main Results:

  • Polθ promotes survival and proliferation in DNMT3Amut leukemia by participating in DSB repair and replication fork restart.
  • Polθ is overexpressed in DNMT3Amut leukemia due to impaired degradation, linked to abrogation of PARP1-mediated ubiquitination.
  • Polθ inhibition synergizes with standard treatments (quizartinib, cytarabine, doxorubicin, etoposide) to enhance anti-leukemic effects.

Conclusions:

  • Polθ is a critical factor for the survival of DNMT3Amut leukemia cells.
  • Targeting Polθ represents a promising therapeutic strategy for DNMT3Amut hematological malignancies, potentially overcoming treatment resistance.
Keywords:
DNA polymerase thetaDNMT3A-deficient acute myeloid leukemiaPARP1TMEJreplication forkubiquitination

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