Polθ activity modulates sensitivity to standard therapies in DNMT3A-deficient leukemia

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 (Pol9), a key element in DSB repair by end-joining (Pol9-mediated end-joining [TMEJ]) and in fork restarting, promotes survival and proliferation of DNMT3Amut leukemia cells. Pol9 is overexpressed in DNMT3Amut leukemia cells due to abrogation of PARP1 PARylation-dependent UBE2O E3 ligase-mediated ubiquitination and proteasomal degradation of Pol9. In addition, PARP1-mediated recruitment of the SMARCAD1-MSH2/ MSH3 repressive complex to DSBs is diminished in DNMT3Amut leukemia cells, which facilitates association of Pol9 with DNA damage. Pol9 inhibitors enhance the anti-leukemic effects of standard drugs such as FLT3 kinase inhibitor quizartinib, cytarabine +/- doxorubicin, and etoposidein vitro and in mice with DNMT3Amut leukemia. Altogether, Pol9 is an attractive target in DNMT3Amut hematological malignancies.

Temple University
Nencki Institute of Experimental Biology
Fox Chase Cancer Center
Université Laval
Washington University in St. Louis
University of North Carolina at Chapel Hill
University of Cambridge
Medizinische Universität Wien - AKH