HSPCs are exposed to low levels of oxygen in the bone marrow niche, and Hypoxia-Inducible Factors (HIFs) are the main regulators of cellular responses to oxygen variation.
Recent studies using conditional knockout mouse models have unveiled a major role for HIF-1α in the maintenance of murine HSCs; however, the role of HIF-2α is still unclear.
We recently demonstrated that knockdown of HIF-2α, and to a much lesser extent HIF-1α, impedes the long-term repopulating ability of human CD34+ umbilical cord blood cells. HIF-2α-deficient HSPCs display increased production of Reactive Oxygen Species (ROS), which subsequently stimulate Endoplasmic Reticulum (ER) stress and triggers apoptosis by activation of the Unfolded-Protein-Response (UPR) pathway (Figure 1). HIF-2α deregulation also significantly decreased engraftment ability of human acute myeloid leukaemia (AML) cells.
Overall, our data demonstrates a key role for HIF-2α in the maintenance of human HSPCs and in the survival of primary AML cells. Whether inhibition of this pathway could be used to selectively target AML has still to be determined (Rouault-Pierreet al., 2013; Cell Stem Cell. 13(5): 549-63)