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: Heidrun Drolle, Michaela Wagner, Jochen Vasold, Alexander Kütt, Christian Deniffel, Karl Sotlar, Silvia Sironi, Tobias Herold, Christina Rieger, Michael Fiegl
• Journal: Leukemia research (Leuk Res) Vol. 39 Issue 7 Pg. 779-85 (Jul 2015) ISSN: 1873-5835 [Electronic] England
• PMID: 25982178 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents

Topics

• Antineoplastic Agents (administration & dosage, therapeutic use)
• Cell Hypoxia
• Humans
• Leukemia, Myeloid, Acute (drug therapy, pathology)