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

Lookup NU author(s): Dr Deepali Pal, Dr Helen BlairORCiD, Professor Olaf Heidenreich

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. 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.

Publication metadata

Author(s): Fidyt K, Pastorczak A, Goral A, Szczygiel K, Fendler W, Muchowicz A, Bartlomiejczyk MA, Madzio J, Cyran J, Graczyk-Jarzynka A, Jansen E, Patkowska E, Lech-Maranda E, Pal D, Blair H, Burdzinska A, Pedzisz P, Glodkowska-Mrowka E, Demkow U, Gawle-Krawczyk K, Matysiak M, Winiarska M, Juszczynski P, Mlynarski W, Heidenreich O, Golab J, Firczuk M

Publication type: Article

Publication status: Published

Journal: Molecular Oncology

Year: 2019

Volume: 13

Issue: 5

Pages: 1180-1195

Print publication date: 01/05/2019

Online publication date: 12/03/2019

Acceptance date: 21/02/2019

Date deposited: 15/05/2019

ISSN (print): 1574-7891

ISSN (electronic): 1878-0261

Publisher: John Wiley and Sons Ltd.

URL: https://doi.org/10.1002/1878-0261.12476

DOI: 10.1002/1878-0261.12476

PubMed id: 30861284

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