title: Hypoxia regulates proliferation of acute myeloid leukemia and sensitivity against chemotherapy.
abstract: Reduced oxygen partial pressure (pO2, hypoxia) is an important component of the bone marrow microenvironment and the hematopoietic stem cell niche. It is unclear whether this applies to the leukemic stem cell as well and if differences in pO2 between the normal hematopoetic and the leukemic stem cell niche exits. Here, we demonstrate that while there is no detectable difference in the hypoxic level of bone marrow infiltrated by acute myeloid leukemia (AML) and healthy bone marrow, physiological hypoxia of 1% O2 itself leads to cell cycle arrest of AML blasts (both cell lines and primary AML samples) in the G0/G1 phase with upregulation of p27 and consecutive decrease of cells in the S phase. Hence, susceptibility of AML blasts toward cytarabine as S phase dependent drug is significantly decreased as shown by decreased cytotoxicity in vitro. In addition, cells exposed to hypoxia activate PI3K/Akt and increase expression of anti-apoptotic XIAP. Inhibition of PI3K can restore cytarabine sensitivity of AML blasts at hypoxic conditions. In conclusion, hypoxia mediated effects encountered in the bone marrow might contribute to chemoresistance of AML blasts.
authors.affiliation: Department of Internal Medicine III, Hospital of the University of Munich, Munich, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Drolle
authors.affiliation: Department of Internal Medicine III, Hospital of the University of Munich, Munich, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Department of Internal Medicine III, Hospital of the University of Munich, Munich, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Vasold
authors.affiliation: Department of Internal Medicine III, Hospital of the University of Munich, Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kütt
authors.affiliation: Department of Internal Medicine III, Hospital of the University of Munich, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Deniffel
authors.affiliation: Institute of Pathology, Hospital of the University of Munich, Munich, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Sotlar
authors.affiliation: Department of Internal Medicine III, Hospital of the University of Munich, Munich, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sironi
authors.affiliation: Department of Internal Medicine III, Hospital of the University of Munich, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Herold
authors.affiliation: Department of Internal Medicine III, Hospital of the University of Munich, Munich, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Rieger
authors.affiliation: Department of Internal Medicine III, Hospital of the University of Munich, Munich, Germany. Electronic address: michael.fiegl@med.uni-muenchen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Fiegl
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D015687:Cell Hypoxia; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents
keywords: Acute myeloid leukemia; Bone marrow; Cell cycle; Chemotherapy; Hypoxia