Targeting the thioredoxin system as a novel strategy against B-cell acute lymphoblastic leukemia

Klaudyna Fidyt, Agata Pastorczak, Agnieszka Goral, Kacper Szczygiel, Wojciech Fendler, Angelika Muchowicz, Marcin Adam Bartlomiejczyk, Joanna Madzio, Julia Cyran, Agnieszka Graczyk-Jarzynka, Eugene Jansen, Elzbieta Patkowska, Ewa Lech-Maranda, Deepali Pal, Helen Blair, Anna Burdzinska, Piotr Pedzisz, Eliza Glodkowska-Mrowka, Urszula Demkow, Karolina Gawle-KrawczykMichal Matysiak, Magdalena Winiarska, Przemyslaw Juszczynski, Wojciech Mlynarski, Olaf Heidenreich, Jakub Golab, Malgorzata Firczuk

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)
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Abstract

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a genetically heterogeneous blood cancer characterized by abnormal expansion of immature B cells. Although intensive chemotherapy provides high cure rates in a majority of patients, subtypes harboring certain genetic lesions, such as MLL rearrangements or BCR-ABL1 fusion, remain clinically challenging, necessitating a search for other therapeutic approaches. Herein, we aimed to validate antioxidant enzymes of the thioredoxin system as potential therapeutic targets in BCP-ALL. We observed oxidative stress along with aberrant expression of the enzymes associated with the activity of thioredoxin antioxidant system in BCP-ALL cells. Moreover, we found that auranofin and adenanthin, inhibitors of the thioredoxin system antioxidant enzymes, effectively kill BCP-ALL cell lines and pediatric and adult BCP-ALL primary cells, including primary cells cocultured with bone marrow-derived stem cells. Furthermore, auranofin delayed the progression of leukemia in MLL-rearranged patient-derived xenograft model and prolonged the survival of leukemic NSG mice. Our results unveil the thioredoxin system as a novel target for BCP-ALL therapy, and indicate that further studies assessing the anticancer efficacy of combinations of thioredoxin system inhibitors with conventional anti-BCP-ALL drugs should be continued.

Original languageEnglish
Pages (from-to)1180-1195
Number of pages16
JournalMolecular Oncology
Volume13
Issue number5
Early online date12 Mar 2019
DOIs
Publication statusPublished - May 2019

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