| First Author | Le BV | Year | 2026 |
| Journal | Cell Rep Med | Volume | 7 |
| Issue | 3 | Pages | 102687 |
| PubMed ID | 41850232 | Mgi Jnum | J:385329 |
| Mgi Id | MGI:8320909 | Doi | 10.1016/j.xcrm.2026.102687 |
| Citation | Le BV, et al. (2026) Poltheta activity modulates sensitivity to standard therapies in DNMT3A-deficient leukemia. Cell Rep Med 7(3):102687 |
| abstractText | 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 (Poltheta), a key element in DSB repair by end-joining (Poltheta-mediated end-joining [TMEJ]) and in fork restarting, promotes survival and proliferation of DNMT3Amut leukemia cells. Poltheta is overexpressed in DNMT3Amut leukemia cells due to abrogation of PARP1 PARylation-dependent UBE2O E3 ligase-mediated ubiquitination and proteasomal degradation of Poltheta. In addition, PARP1-mediated recruitment of the SMARCAD1-MSH2/MSH3 repressive complex to DSBs is diminished in DNMT3Amut leukemia cells, which facilitates association of Poltheta with DNA damage. Poltheta 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, Poltheta is an attractive target in DNMT3Amut hematological malignancies. |
