MECHANISMS OF HYPOXIA-INDUCED GROWTH AND TYROSINE KINASE INHIBITOR RESISTANCE IN CHRONIC MYELOID LEUKEMIA

Abstract

Resistance to tyrosine kinase inhibitors (TKIs) remains a problem in treatment of chronic myeloid leukemia (CML) patients. CML leukemic stem cells (LSC) are insensitive to TKIs, and reside in hypoxic niches in the bone marrow. In this study, we investigate the contribution of hypoxia to TKI resistance in CML.

We found that hypoxia (0.5% O2) causes resistance to TKIs in CML cells. The degree of resistance was dependent on duration of hypoxia, and cells exposed to long-term hypoxia were more resistant than short-term hypoxia cells. Adaptation to long-term hypoxic culture was associated with recovery of mTORC activity and translation compared to short-term hypoxia cells. We also found that the hypoxia-inducible transcription factors, HIF1a and HIF2a, were important for survival, colony formation and TKI-resistance. Finally, we found that HIF target, Arginase 2 (ARG2), was upregulated under hypoxia specifically in CML cells. Inhibition of ARG2 with inhibitor, nor-NOHA, suppressed proliferation of CML cells under hypoxia, demonstrating a role for this pathway in survival under hypoxic conditions.