Hypoxic conditions confer chemoresistance to crizotinib but not to imatinib in chronic myeloid leukemia cells

Abstract

Introduction: Chronic myeloid leukemia is an adult leukemia, constituting 15 % of all leukemia diagnoses. The fundamental driver of disease pathogenesis is the Bcr/Abl fusion protein, characterized by dysregulated tyrosine kinase activity. Abl kinase inhibitors have become the mainstay of treatment, however, patients often develop resistance due to genetic alterations, particularly affecting the Bcr/Abl oncoprotein. The tumor microenvironment is also associated with acquired resistance to Abl kinase inhibitors in chronic myeloid leukemia. Methods: The influence of hypoxic conditions on the development of chemoresistance to certain Abl kinase inhibitors was investigated in chronic myeloid leukemia. Results: This study showed that hypoxia increased resistance to crizotinib, while imatinib resistance was modest. Both drugs effectively inhibited Bcr/Abl activity. Interestingly, the JAK1/2 inhibitor ruxolitinib further enhanced chemoresistance to crizotinib under hypoxic conditions. Hypoxia-inducible factor 1α (HIF1α) overexpression in JAK2 knockdown experiments confirmed their cooperative role in mediating crizotinib resistance. In addition, 2-methoxyestradiol, a non-estrogenic estradiol metabolite, restored crizotinib sensitivity under hypoxia and the combination of 2-methoxyestradiol with a JAK2 inhibitor showed promising results in overcoming crizotinib resistance. Conclusion: In summary, this study shows the critical role of selective targeting of components of the HIF1α signaling pathway for the complete eradication of chronic myeloid leukemia cells.