European Journal of Haematology, September 2016, Vol.97(3), pp.239-244
Byline: Nicole Degwert, Emily Latuske, Gabi Vohwinkel, Hauke Stamm, Marianne Klokow, Carsten Bokemeyer, Walter Fiedler, Jasmin Wellbrock Keywords: Acute myeloid leukaemia; hypoxia; drug resistance; deoxycytidine kinase; hypoxia-inducible factor 1 alpha Abstract Objectives Leukaemia initiating cells reside within specialised niches in the bone marrow where they undergo complex interactions with different stromal cell types. The bone marrow niche is characterised by a low oxygen content resulting in high expression of hypoxia-inducible factor 1 [alpha] in leukaemic cells conferring a negative prognosis to patients with acute myeloid leukaemia (AML). Methods and Results In the current study, we investigated the impact of hypoxic vs. normoxic conditions on the sensitivity of AML cell lines and primary AML blasts to cytarabine. AML cells cultured under 6% oxygen were significantly more resistant against cytarabine compared to cells cultured under normoxic conditions in proliferation and colony-formation assays. Interestingly upon cultivation under hypoxia, the expression of the cytarabine-activating enzyme deoxycytidine kinase was downregulated in all analysed AML cell lines and primary AML samples representing a possible mechanism for resistance to chemotherapy. Furthermore, the downregulation of deoxycytidine kinase could be associated with hypoxia-inducible factor 1 [alpha] as treatment with its inhibitor BAY87-2243 hampered the downregulation of deoxycytidine kinase expression under hypoxic conditions. Conclusions In conclusion, our data reveal that hypoxia-induced downregulation of deoxycytidine kinase represents one stroma-cell-independent mechanism of drug resistance to cytarabine in acute myeloid leukaemia. Article Note: Contributed equally to the work.
Acute Myeloid Leukaemia ; Hypoxia ; Drug Resistance ; Deoxycytidine Kinase ; Hypoxia‐Inducible Factor 1 Alpha