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While tyrosine kinase inhibitors (TKIs) are effective in up to 95% of CML patients, 50% of Ph<jats:sup>+<\/jats:sup> B\u2010ALL cases do not respond to treatment or relapse. This calls for new therapeutic approaches for Ph<jats:sup>+<\/jats:sup> B\u2010ALL. Previous studies have shown that inhibitors of the thioredoxin (TXN) system exert antileukemic activity against B\u2010ALL cells, particularly in combination with other drugs. Here, we present that peroxiredoxin\u20101 (PRDX1), one of the enzymes of the TXN system, is upregulated in Ph<jats:sup>+<\/jats:sup> lymphoid as compared to Ph<jats:sup>+<\/jats:sup> myeloid cells. <jats:italic>PRDX1<\/jats:italic> knockout negatively affects the viability of Ph<jats:sup>+<\/jats:sup> B\u2010ALL cells and sensitizes them to TKIs. Analysis of global gene expression changes in imatinib\u2010treated, PRDX1\u2010deficient cells revealed that the nonhomologous end\u2010joining (NHEJ) DNA repair is a novel vulnerability of Ph<jats:sup>+<\/jats:sup> B\u2010ALL cells. Accordingly, PRDX1\u2010deficient Ph<jats:sup>+<\/jats:sup> B\u2010ALL 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<jats:sup>+<\/jats:sup> B\u2010ALL cell lines and primary cells, which can be further investigated as a potential therapeutic approach for the treatment of Ph<jats:sup>+<\/jats:sup> B\u2010ALL.<\/jats:p>","DOI":"10.1002\/hem3.56","type":"journal-article","created":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T10:57:40Z","timestamp":1710413860000},"source":"Crossref","is-referenced-by-count":3,"title":["Concomitant inhibition of the thioredoxin system and nonhomologous DNA repair potently sensitizes Philadelphia\u2010positive lymphoid leukemia to tyrosine kinase inhibitors"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7646-1968","authenticated-orcid":false,"given":"Lukasz","family":"Komorowski","sequence":"first","affiliation":[{"name":"Department of Immunology Medical University of Warsaw Warsaw 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