2. Academic Validation
  3. DNA polymerase theta-mediated DNA repair is a functional dependency and therapeutic vulnerability in DNMT3A deficient leukemia cells

DNA polymerase theta-mediated DNA repair is a functional dependency and therapeutic vulnerability in DNMT3A deficient leukemia cells

  • bioRxiv. 2024 Sep 19:2024.09.15.613155. doi: 10.1101/2024.09.15.613155.
Bac Viet Le,  Umeshkumar Vekariya,  Monika M Toma,  Margaret Nieborowska-Skorska,  Marie-Christine Caron,  Malgorzata Gozdecka,  Zayd Haydar,  Martin Walsh,  Jayashri Ghosh,  Elaine Vaughan-Williams,  Paulina Podszywalow-Bartnicka,  Anna-Mariya Kukuyan,  Sylwia Ziolkowska,  Emir Hadzijusufovic,  Gurushankar Chandramouly,  Katarzyna Piwocka,  Richard Pomerantz,  George S Vassiliou,  Brian Jp Huntly,  Peter Valent,  Alfonso Bellacosa,  Jean-Yves Masson,  Gaorav P Gupta,  Grant A Challen,  Tomasz Skorski
PMID: 39411165 DOI: 10.1101/2024.09.15.613155
Abstract

Myeloid malignancies carrying somatic DNMT3A mutations (DNMT3Amut) are usually resistant to standard therapy. DNMT3Amut leukemia cells accumulate toxic DNA double strand breaks (DSBs) and collapsed replication forks, rendering them dependent on DNA damage response (DDR). DNA Polymerase theta (Polθ), a key element in Polθ-mediated DNA end-joining (TMEJ), is essential for 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 was diminished in DNMT3Amut leukemia cells which facilitated loading of Polθ on DNA damage and promoting TMEJ and replication fork restart. Polθ inhibitors enhanced the anti-leukemic effects of mainstream drugs such as FLT3 kinase inhibitor quizartinib, cytarabine and etoposide in vitro and in mice with FLT3(ITD);DNMT3Amut leukemia. Altogether, Polθ is an attractive target in DNMT3Amut hematological malignancies.

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