https://phaidra.vetmeduni.ac.at/o:5434 Polθ activity modulates sensitivity to standard therapies in DNMT3A-deficient leukemia Le, Bac Viet Bac Viet Le Vekariya, Umeshkumar Umeshkumar Vekariya Toma, Monika M. Monika M. Toma Nieborowska-Skorska, Margaret Margaret Nieborowska-Skorska Caron, Marie-Christine Marie-Christine Caron Gozdecka, Malgorzata Malgorzata Gozdecka Haydar, Zayd Zayd Haydar Walsh, Martin Martin Walsh Ghosh, Jayashri Jayashri Ghosh Vaughan-Williams, Elaine Elaine Vaughan-Williams Podszywalow-Bartnicka, Paulina Paulina Podszywalow-Bartnicka Kukuyan, Anna-Mariya Anna-Mariya Kukuyan Ziolkowska, Sylwia Sylwia Ziolkowska Atkins, Jessica Jessica Atkins Hadzijusufovic, Emir Emir Hadzijusufovic 0000-0001-7409-4204 University of Veterinary Medicine Vienna. Clinical Centre for Small Animal Health and Research Chandramouly, Gurushankar Gurushankar Chandramouly Nejati, Reza Reza Nejati Piwocka, Katarzyna Katarzyna Piwocka Pomerantz, Richard Richard Pomerantz Vassiliou, George S. George S. Vassiliou Huntly, Brian J.P. Brian J.P. Huntly Valent, Peter Peter Valent Wasik, Mariusz Mariusz Wasik Bellacosa, Alfonso Alfonso Bellacosa Masson, Jean-Yves Jean-Yves Masson Gupta, Gaorav P. Gaorav P. Gupta Challen, Grant A. Grant A. Challen Skorski, Tomasz Tomasz Skorski 0000-0002-3809-4538 Elsevier journal article open access eng 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. DNA Polymerase Theta DNMT3A-deficient Acute Myeloid Leukemia PARP1 TMEJ Replication Fork Ubiquitination http://creativecommons.org/licenses/by-nc-nd/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:5434/download 10.1016/j.xcrm.2026.102687 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Cell Reports Medicine issn:2666-3791 VoR Cell Reports Medicine 7 3 9.27 MB 2026