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

Breakpoint cluster region-Abelson () gene fusion is an essential oncogene in both chronic myeloid leukemia (CML) and Philadelphia-positive (Ph) B-cell acute lymphoblastic leukemia (B-ALL). While tyrosine kinase inhibitors (TKIs) are effective in 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. Previous studies have shown that inhibitors of the thioredoxin (TXN) system exert antileukemic activity against B-ALL cells, particularly in combination with other drugs. Here, we present that peroxiredoxin-1 (PRDX1), one of the enzymes of the TXN system, is upregulated in Ph lymphoid as compared to Ph myeloid cells. knockout negatively affects the viability of Ph B-ALL cells and sensitizes them to TKIs. Analysis of global gene expression changes in imatinib-treated, PRDX1-deficient cells revealed that the nonhomologous end-joining (NHEJ) DNA repair is a novel vulnerability of Ph B-ALL cells. Accordingly, PRDX1-deficient Ph B-ALL cells were susceptible to NHEJ inhibitors. Finally, we demonstrated the potent efficacy of a novel combination of TKIs, TXN inhibitors, and NHEJ inhibitors against Ph B-ALL cell lines and primary cells, which can be further investigated as a potential therapeutic approach for the treatment of Ph B-ALL.