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

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; Malgorzata Firczuk

doi:10.1002/hem3.56

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

Hemasphere. 2024 Mar 14;8(3):e56. doi: 10.1002/hem3.56. eCollection 2024 Mar.

Authors

Lukasz Komorowski^{1

2}, Agnieszka Dabkowska^{1

3}, Joanna Madzio⁴, Agata Pastorczak⁴, Kacper Szczygiel^{1

5}, Martyna Janowska³, Klaudyna Fidyt¹, Maksymilian Bielecki⁶, Jaromir Hunia¹, Malgorzata Bajor³, Tomasz Stoklosa⁷, Magdalena Winiarska^{1

3}, Elzbieta Patkowska⁸, Malgorzata Firczuk^{1

3}

Affiliations

¹ Department of Immunology Medical University of Warsaw Warsaw Poland.
² Postgraduate School of Molecular Medicine Medical University of Warsaw Warsaw Poland.
³ Laboratory of Immunology, Mossakowski Medical Research Institute Polish Academy of Sciences Warsaw Poland.
⁴ Department of Pediatrics, Oncology and Hematology Medical University of Lodz Lodz Poland.
⁵ Polpharma Biologics SA Gdańsk Poland.
⁶ Department of Psychology SWPS University of Social Sciences and Humanities Warsaw Poland.
⁷ Department of Tumor Biology and Genetics Medical University of Warsaw Warsaw Poland.
⁸ Institute of Hematology and Transfusion Medicine Warsaw Poland.

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.