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

      Fidyt, Klaudyna; Pastorczak, Agata; Goral, Agnieszka; Szczygiel, Kacper; Fendler, Wojciech; Muchowicz, Angelika; Bartlomiejczyk, Marcin Adam; Madzio, Joanna; Cyran, Julia; Graczyk-Jarzynka, Agnieszka; Jansen, Eugene; Patkowska, Elzbieta; Lech-Maranda, Ewa; Pal, Deepali; Blair, Helen; Burdzinska, Anna; Pedzisz, Piotr; Glodkowska-Mrowka, Eliza; Demkow, Urszula; Gawle-Krawczyk, Karolina; Matysiak, Michal; Winiarska, Magdalena; Juszczynski, Przemyslaw; Mlynarski, Wojciech; Heidenreich, Olaf; Golab, Jakub; Firczuk, Malgorzata (2019-03-12)
      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 co-cultured 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.