The Effect of BCR-ABL Specific Tyrosine Kinase Inhibitors on the Thioredoxin System in Chronic Myeloid Leukemia

Erin Clapper,Giovanna Di Trapani,Kathryn F Tonissen

doi:10.3390/hemato2020014

Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative disorder that is caused by the formation of a fusion onco-protein, BCR-ABL. Since BCR-ABL plays a role in the progression of CML, the most common treatments of CML are tyrosine kinase inhibitors (TKIs) that specifically target BCR-ABL. However, resistance to TKIs is a major problem in CML treatment. A promising target in overcoming drug resistance in other cancers is the thioredoxin (TRX) system, an antioxidant system that maintains cellular redox homeostasis. The TRX system is upregulated in many cancers and this is associated with a poor prognosis. Analysis of a patient database showed that the expression of the TRX system was upregulated in CML patients compared to healthy donors. Our experiments revealed a significant link between the TRX and BCR-ABL systems since inhibition of BCR-ABL with chemical inhibitors and siRNA resulted in a decrease in the activity and expression of the TRX system in CML cells. This is notable as it shows that the TRX system may be a viable target in the treatment of CML.

Highlights

Chronic myeloid leukemia (CML) is a cancer of myeloid cells that is caused by a reciprocal chromosomal translocation between chromosomes 9 and 22
It has been reported in many cancers, such as breast and gastric cancers, that TRX1 expression levels are upregulated, and this has been associated with a poor prognosis [17,45,46]
This current study has shown that TRX1 is upregulated in both CML cell lines and in patient samples, in the terminal and most severe stage of CML, blast crisis

Summary

Introduction

Chronic myeloid leukemia (CML) is a cancer of myeloid cells that is caused by a reciprocal chromosomal translocation between chromosomes 9 and 22. This mutation results in the formation of BCR-ABL, which is a constitutively active non-receptor tyrosine kinase. BCR-ABL is responsible for the majority of the clinical manifestations of CML. This is because BCR-ABL activates various cell survival pathways, including the JAK/STAT, AKT and PKC pathways, which induce downstream signaling that leads to increased cell proliferation and survival and lower levels of apoptosis [1,2,3]. Since most CML treatments are BCR-ABL specific, this results in high levels of acquired drug resistance, due primarily to mutations within BCR-ABL [5,6,7]

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