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

Research output: Contribution to journalArticle

DOI

Authors

  • 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
  • Helen Blair
  • Anna Burdzinska
  • Piotr Pedzisz
  • Eliza Glodkowska-Mrowka
  • Urszula Demkow
  • Karolina Gawle-Krawczyk
  • Michal Matysiak
  • Magdalena Winiarska
  • Przemyslaw Juszczynski
  • Wojciech Mlynarski
  • Olaf Heidenreich
  • Jakub Golab
  • Malgorzata Firczuk

Departments

External departments

  • Medical University of Warsaw
  • Medical University of Łódź
  • Dana-Farber Cancer Institute
  • National Institute for Public Health and the Environment
  • Institute of Hematology and Transfusion Medicine
  • Centre of Postgraduate Medical Education
  • Newcastle University

Details

Original languageEnglish
JournalMolecular Oncology
Early online date12 Mar 2019
DOIs
Publication statusE-pub ahead of print - 12 Mar 2019
Publication type

Research output: Contribution to journalArticle

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.

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