HIF-2α Protects Human Hematopoietic Stem/Progenitors and Acute Myeloid Leukemic Cells from Apoptosis Induced by Endoplasmic Reticulum Stress

Hematopoietic stem and progenitor cells (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-1 alpha in the maintenance of murine HSCs; however, the role of HIF-2 alpha is still unclear. Here, we show that knockdown of HIF-2 alpha, and to a much lesser extent HIF-1 alpha, impedes the long-term repopulating ability of human CD34(+) umbilical cord blood cells. HIF-2 alpha-deficient HSPCs display increased production of reactive oxygen species (ROS), which subsequently stimulates endoplasmic reticulum (ER) stress and triggers apoptosis by activation of the unfolded-protein-response (UPR) pathway. HIF-2 alpha deregulation also significantly decreased engraftment ability of human acute myeloid leukemia (AML) cells. Overall, our data demonstrate a key role for HIF-2 alpha in the maintenance of human HSPCs and in the survival of primary AML cells.