Bac Viet Le Bac Viet Le Umeshkumar Vekariya Umeshkumar Vekariya Monika M. Toma Monika M. Toma Margaret Nieborowska-Skorska Margaret Nieborowska-Skorska Marie-Christine Caron Marie-Christine Caron Malgorzata Gozdecka Malgorzata Gozdecka Zayd Haydar Zayd Haydar Martin Walsh Martin Walsh Jayashri Ghosh Jayashri Ghosh Elaine Vaughan-Williams Elaine Vaughan-Williams Paulina Podszywalow-Bartnicka Paulina Podszywalow-Bartnicka Anna-Mariya Kukuyan Anna-Mariya Kukuyan Sylwia Ziolkowska Sylwia Ziolkowska Jessica Atkins Jessica Atkins Emir Hadzijusufovic (Clinical Centre for Small Animal Health and Research, Clinical Department for Small Animals and Horses, Departments, University of Veterinary Medicine Vienna) Emir Hadzijusufovic Gurushankar Chandramouly Gurushankar Chandramouly Reza Nejati Reza Nejati Katarzyna Piwocka Katarzyna Piwocka Richard Pomerantz Richard Pomerantz George S. Vassiliou George S. Vassiliou Brian J.P. Huntly Brian J.P. Huntly Peter Valent Peter Valent Mariusz Wasik Mariusz Wasik Alfonso Bellacosa Alfonso Bellacosa Jean-Yves Masson Jean-Yves Masson Gaorav P. Gupta Gaorav P. Gupta Grant A. Challen Grant A. Challen Tomasz Skorski Tomasz Skorski Elsevier 2026 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. PDFDocument eng 2026-08-19T08:20:12.882918556Z 2026 DNA Polymerase Theta DNMT3A-deficient Acute Myeloid Leukemia PARP1 TMEJ Replication Fork Ubiquitination 9718790 b application/pdf http://creativecommons.org/licenses/by-nc-nd/4.0/