Concomitant inhibition of the thioredoxin system and non-homologous DNA repair potently sensitizes Philadelphia-positive lymphoid leukemia to tyrosine kinase inhibitors

BCR-ABL1 gene fusion is an essential driver lesion in both chronic myeloid leukemia (CML) and Philadelphia-positive (Ph+) B-cell acute lymphoblastic leukemia (B-ALL). While tyrosine kinase inhibitors (TKIs) cure up to 95% of CML patients, 50 % of Ph+ B-ALL cases do not respond to treatment or relapse. This calls for new therapeutic approaches for Ph+ B-ALL. Dysregulated redox homeostasis manifested by the increased reactive oxygen species (ROS) levels and the upregulation of the thioredoxin (TXN) antioxidant system has been previously shown in B-ALL. Pharmacological inhibition of the TXN system with auranofin (AUR) efficiently kills B-ALL cells, indicating that the TXN system plays a major role in maintaining redox homeostasis in B-ALL cells. Here we show that peroxiredoxin-1 (PRDX1), one of the enzymes of the TXN system responsible for scavenging H2O2, is upregulated in Ph+ lymphoid as compared to Ph+ myeloid cells. The genomic knockout of PRDX1 negatively affects the viability of Ph+ B-ALL cells and sensitizes them to TKIs, while no such effects occur in myeloid cells. By analyzing global changes in gene expression in PRDX1-deficient cells treated with imatinib we discover non-homologous end-joining (NHEJ) DNA repair pathways as a novel vulnerability of Ph+ B-ALL cells. Accordingly, pharmacologic inhibition of the TXN system diminishes the viability of Ph+ B-ALL cells and enhances their sensitivity to TKIs and NHEJ inhibitors. Finally, we propose a novel combination of TKIs, TXN inhibitors, and NHEJ inhibitors as a potential therapeutic approach for the treatment of Ph+ B-ALL.