The regulation of bcr-abl in hypoxia is through the mTOR pathway

Abstract

Chronic myeloid leukemia (CML) is usually characterized by the formation of the fusion onco-protein bcr-abl. Therefore, the majority of CML treatments are bcr-abl specific tyrosine kinase inhibitors (TKIs). TKI resistance in CML treatment is becoming a major obstacle in managing this disease. One well-studied form of drug resistance is hypoxia-induced drug resistance, a phenomenon observed in many other cancers. This study aimed to determine the efficacy of TKIs in CML cells cultured in hypoxia. It was observed that bcr-abl translation was severely halted in hypoxia, rendering TKIs ineffective. We found that the mechanism by which bcr-abl protein levels were being suppressed in hypoxia was through the mTOR pathway, specifically via ribosomal protein S6 (RPS6). This information is vital to the improvement of CML treatments, as it can be used to determine how to best combat hypoxia-induced drug resistance in CML and subsequently to identify new targets for treatment.

Keywords:

• Chronic myeloid leukemia
• CML
• hypoxia
• bcr-abl
• drug resistance

Acknowledgments

The authors thank Dr. Chris Slape (Translational Research Institute, QLD, Australia) for supplying us with the K562 cell line.

Author contributions

E.C. carried out overall project design experimental work, analyzed results and wrote the manuscript. G.D. and K.T. both supervised the design and conduct of the project and were involved in the editing and reviewing of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

E.C. is a recipient of the Australian Government Research Training Program scholarship. Funding for the research was provided by Griffith University.