Journal
LEUKEMIA RESEARCH
Volume 39, Issue 7, Pages 779-785Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.leukres.2015.04.019
Keywords
Acute myeloid leukemia; Bone marrow; Hypoxia; Chemotherapy; Cell cycle
Categories
Funding
- German Research foundation [DFG FI 1487/2]
- Wilhelm Sander-Foundation [2013.005.1]
Ask authors/readers for more resources
Reduced oxygen partial pressure (pO(2),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 pO(2) 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% O-2 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. (C) 2015 Elsevier Ltd. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available