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<lom:identifier>
  
<lom:catalog>DOI</lom:catalog>

  
<lom:entry>
  
<lom:langstring xml:lang="x-none">10.1016/j.xcrm.2026.102687</lom:langstring>

  
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</lom:identifier>

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

  
</lom:title>

  
<lom:description>
  
<lom:langstring 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.</lom:langstring>

  
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<lom:language>eng</lom:language>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">DNA Polymerase Theta</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">DNMT3A-deficient Acute Myeloid Leukemia</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">PARP1</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">TMEJ</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">Replication Fork</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">Ubiquitination</lom:langstring>

  
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<lom:datetime>2026-08-19T08:20:13.078Z</lom:datetime>

  
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<lom:vcard>BEGIN:VCARD
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N:Le;Bac Viet;
FN:Bac Viet Le
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N:Vekariya;Umeshkumar;
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N:Toma;Monika M.;
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N:Nieborowska-Skorska;Margaret;
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N:Caron;Marie-Christine;
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N:Gozdecka;Malgorzata;
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N:Haydar;Zayd;
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N:Walsh;Martin;
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N:Ghosh;Jayashri;
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N:Vaughan-Williams;Elaine;
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N:Kukuyan;Anna-Mariya;
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N:Ziolkowska;Sylwia;
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N:Atkins;Jessica;
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N:Hadzijusufovic;Emir;
FN:Emir Hadzijusufovic
X-ORCID:https://orcid.org/0000-0001-7409-4204
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N:Nejati;Reza;
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N:Piwocka;Katarzyna;
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N:Pomerantz;Richard;
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N:Vassiliou;George S.;
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N:Huntly;Brian J.P.;
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N:Valent;Peter;
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N:Wasik;Mariusz;
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N:Bellacosa;Alfonso;
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N:Masson;Jean-Yves;
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N:Gupta;Gaorav P.;
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N:Challen;Grant A.;
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N:Skorski;Tomasz;
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X-ORCID:https://orcid.org/0000-0002-3809-4538
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