1. Concomitant inhibition of the thioredoxin system and nonhomologous DNA repair potently sensitizes Philadelphia‐positive lymphoid leukemia to tyrosine kinase inhibitors
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Lukasz Komorowski, Agnieszka Dabkowska, Joanna Madzio, Agata Pastorczak, Kacper Szczygiel, Martyna Janowska, Klaudyna Fidyt, Maksymilian Bielecki, Jaromir Hunia, Malgorzata Bajor, Tomasz Stoklosa, Magdalena Winiarska, Elzbieta Patkowska, and Malgorzata Firczuk
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract Breakpoint cluster region‐Abelson (BCR::ABL1) 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. PRDX1 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.
- Published
- 2024
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