Polθ activity modulates sensitivity to standard therapies in DNMT3A-deficient leukemia - PubMed
5 hours ago
- #Polθ
- #DNMT3A
- #leukemia
- DNMT3A-mutated myeloid malignancies are resistant to standard therapies.
- Polθ (DNA polymerase theta) is overexpressed in DNMT3A-mutated leukemia cells, aiding their survival and proliferation.
- Polθ's overexpression is due to disrupted PARP1 PARylation, leading to reduced ubiquitination and degradation of Polθ.
- DNMT3A-mutated cells show diminished recruitment of the SMARCAD1-MSH2/MSH3 complex to DNA damage sites, facilitating Polθ's role in repair.
- Polθ inhibitors enhance the effectiveness of standard leukemia drugs like quizartinib, cytarabine, doxorubicin, and etoposide in vitro and in vivo.
- Polθ is identified as a promising therapeutic target in DNMT3A-mutated hematological malignancies.