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<dc:title xml:lang="en">Polθ activity modulates sensitivity to standard therapies in DNMT3A-deficient leukemia</dc:title>

  
<dc:description xml:lang="en">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.</dc:description>

  
<dc:identifier rdf:resource="https://phaidra.vetmeduni.ac.at/o:5434"></dc:identifier>

  
<dc:language>en</dc:language>

  
<edm:type>TEXT</edm:type>

  
<dc:type>journal article</dc:type>

  
<dc:type>Wissenschaftlicher Artikel</dc:type>

  
<dc:type>Articolo scientifico</dc:type>

  
<dc:type xml:lang="en">Text</dc:type>

  
<dc:type xml:lang="en">journal article</dc:type>

  
<dc:type xml:lang="it">Documento PDF</dc:type>

  
<dc:type xml:lang="it">Articolo scientifico</dc:type>

  
<dc:type xml:lang="de">Text</dc:type>

  
<dc:type xml:lang="de">Wissenschaftlicher Artikel</dc:type>

  
<dc:subject xml:lang="en">DNA Polymerase Theta</dc:subject>

  
<dc:subject xml:lang="en">DNMT3A-deficient Acute Myeloid Leukemia</dc:subject>

  
<dc:subject xml:lang="en">PARP1</dc:subject>

  
<dc:subject xml:lang="en">TMEJ</dc:subject>

  
<dc:subject xml:lang="en">Replication Fork</dc:subject>

  
<dc:subject xml:lang="en">Ubiquitination</dc:subject>

  
<dcterms:issued>2026</dcterms:issued>

  
<dc:date>2026</dc:date>

  
<dc:creator>Bac Viet Le</dc:creator>

  
<dc:creator>Umeshkumar Vekariya</dc:creator>

  
<dc:creator>Monika M. Toma</dc:creator>

  
<dc:creator>Margaret Nieborowska-Skorska</dc:creator>

  
<dc:creator>Marie-Christine Caron</dc:creator>

  
<dc:creator>Malgorzata Gozdecka</dc:creator>

  
<dc:creator>Zayd Haydar</dc:creator>

  
<dc:creator>Martin Walsh</dc:creator>

  
<dc:creator>Jayashri Ghosh</dc:creator>

  
<dc:creator>Elaine Vaughan-Williams</dc:creator>

  
<dc:creator>Paulina Podszywalow-Bartnicka</dc:creator>

  
<dc:creator>Anna-Mariya Kukuyan</dc:creator>

  
<dc:creator>Sylwia Ziolkowska</dc:creator>

  
<dc:creator>Jessica Atkins</dc:creator>

  
<dc:creator>Emir Hadzijusufovic (Clinical Centre for Small Animal Health and Research, Clinical Department for Small Animals and Horses, Departments, University of Veterinary Medicine Vienna)</dc:creator>

  
<dc:creator>Gurushankar Chandramouly</dc:creator>

  
<dc:creator>Reza Nejati</dc:creator>

  
<dc:creator>Katarzyna Piwocka</dc:creator>

  
<dc:creator>Richard Pomerantz</dc:creator>

  
<dc:creator>George S. Vassiliou</dc:creator>

  
<dc:creator>Brian J.P. Huntly</dc:creator>

  
<dc:creator>Peter Valent</dc:creator>

  
<dc:creator>Mariusz Wasik</dc:creator>

  
<dc:creator>Alfonso Bellacosa</dc:creator>

  
<dc:creator>Jean-Yves Masson</dc:creator>

  
<dc:creator>Gaorav P. Gupta</dc:creator>

  
<dc:creator>Grant A. Challen</dc:creator>

  
<dc:creator>Tomasz Skorski</dc:creator>

  
<dc:publisher>Elsevier</dc:publisher>

  
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