title: Deoxycytidine kinase is downregulated under hypoxic conditions and confers resistance against cytarabine in acute myeloid leukaemia.
abstract: OBJECTIVE
  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 α in leukaemic cells conferring a negative prognosis to patients with acute myeloid leukaemia (AML).
  
  
  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 α 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.
authors.affiliation: Department of Oncology, Haematology and Bone Marrow Transplantation with section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Degwert
authors.affiliation: Department of Oncology, Haematology and Bone Marrow Transplantation with section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Emily
authors.initials: E
authors.lastname: Latuske
authors.affiliation: Department of Oncology, Haematology and Bone Marrow Transplantation with section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Gabi
authors.initials: G
authors.lastname: Vohwinkel
authors.affiliation: Department of Oncology, Haematology and Bone Marrow Transplantation with section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Hauke
authors.initials: H
authors.lastname: Stamm
authors.affiliation: Department of Oncology, Haematology and Bone Marrow Transplantation with section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Klokow
authors.affiliation: Department of Oncology, Haematology and Bone Marrow Transplantation with section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: Department of Oncology, Haematology and Bone Marrow Transplantation with section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
authors.affiliation: Department of Oncology, Haematology and Bone Marrow Transplantation with section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Wellbrock
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology / Q000627:therapeutic use*; D003842:Deoxycytidine Kinase / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D003561:Cytarabine; D003842:Deoxycytidine Kinase
keywords: Acute myeloid leukaemia; deoxycytidine kinase; drug resistance; hypoxia; hypoxia-inducible factor 1 alpha