Submitted June 5, 2008
Accepted October 18, 2008
CXCR4 expression and biological activity in acute myeloid leukemia are dependent on oxygen partial pressure
Michael Fiegl, Ismael Samudio, Karen Clise-Dwyer, Jared K Burks, Zakar Mnjoyan, and Michael Andreeff*
Molecular Hematology & Therapy, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M. D. Anderson Cancer Center, Houston, TX, United States
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: mandreef{at}mdanderson.org.
The CXCR4/SDF-1 axis has been extensively studied because of its role in development and hematopoiesis. In acute myeloid leukemia (AML), elevated expression of CXCR4 has been shown to correlate with shortened survival. While hypoxia increases CXCR4 in several tumor models, the impact of reduced O2 partial pressure (pO2) on expression and biological function of CXCR4 in AML is unknown. We determined the pO2 in bone marrows of AML patients as 6.1% (±1.7). At this pO2, CXCR4 surface and total expression was up-regulated within 10 hours in leukemic cell lines and patient samples as shown by Western blotting, FACS and microscopy. Interestingly, hypoxic cells failed to internalize CXCR4 in response to SDF-1, and upon re-oxygenation at 21% O2, surface and total expression of CXCR4 rapidly decreased independent of ATP or proteasome activity. Instead, increased pO2 lead to alterations of lipid rafts by depletion of cholesterol and structural changes and was associated with increased shedding of CXCR4 positive microparticles, suggesting a novel mechanism of CXCR4 regulation. Given the importance of CXCR4 in cell signaling, survival and adhesion in leukemia, the results suggest that pO2 be considered a critical variable in conducting and interpreting studies of CXCR4 expression and regulation in leukemias.
