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

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.

cROSsing the Line: Between Beneficial and Harmful Effects of Reactive Oxygen Species in B-Cell Malignancies

“…The accumulation of oxidation products of phospholipids and/or DNA in serum as well as elevated levels of intracellular ROS in malignant B cells were observed in patients suffering from CLL ( 4 , 15 , 16 ). Recently, the increased levels of oxidative stress biomarkers were also found in B-ALL ( 6 ) and different types of non-Hodgkin lymphoma (NHL) ( 3 ).…”

“…Enzymes most frequently activated in B-cell malignancies belong to the TXN family. PRDX1 and PRDX2 are upregulated in Burkitt lymphoma cells ( 39 ), PRDX1 and PRDX3 in primary CLL cells ( 10 , 40 ), PRDX1 and TXN1 in B-ALL cells ( 6 ), and TXN1 in the OXPHOS-DLBCL ( 41 ). The increase of antioxidant response in B-ALL occurs also via serine/threonine-protein phosphatase 2A (PP2A), which negatively regulates protein kinase B (AKT) and thus activates other key transcription factors promoting antioxidant response—the Forkhead box proteins (FOXO1 and FOXO3a).…”

“…Primary CLL and B-ALL cells undergo apoptosis when grown in vitro without stromal support ( 40 , 42 ). The co-cultures with stromal cell lines, primary mesenchymal stem cells (MSC) ( 6 ) or adipocytes ( 43 ), promote survival of primary CLL and B-ALL cells and increase their resistance to therapies ( 43 , 44 ). Tumor-stroma interactions occur on many levels ( 45 ).…”

Targeting the MAPK/ERK and PI3K/AKT Signaling Pathways Affects NRF2, Trx and GSH Antioxidant Systems in Leukemia Cells

“…On the other hand, in HL60 and THP-1 AML cell lines, basal HO-1 expression was shown to be relatively low but easily activated upon oxidative stress [26]. The thioredoxin antioxidant system is composed of several proteins, including thioredoxin, and thioredoxin reductase (TrxR), which play an important role in regulating cellular redox homeostasis, cell growth and apoptosis [27,28]. Thioredoxin-1, a cytoplasmic isoform, has been found to activate the PI3K/AKT pathway, thus regulating many cellular processes, such as cell proliferation, migration, and survival [18,27,29].…”

“…The thioredoxin antioxidant system is composed of several proteins, including thioredoxin, and thioredoxin reductase (TrxR), which play an important role in regulating cellular redox homeostasis, cell growth and apoptosis [27,28]. Thioredoxin-1, a cytoplasmic isoform, has been found to activate the PI3K/AKT pathway, thus regulating many cellular processes, such as cell proliferation, migration, and survival [18,27,29]. Both Trx and TrxR expression have been shown to be elevated in ALL and AML cells, and correlated with cell survival and resistance to apoptosis [30,31].…”