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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)1180-1195
Aantal pagina's16
TijdschriftMolecular oncology
Volume13
Nummer van het tijdschrift5
DOI's
StatusGepubliceerd - mei 2019
Extern gepubliceerdJa

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