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

• Published in: Cell stem cell 2013-11, Vol.13 (5), p.549-563
• Main Authors: Rouault-Pierre, Kevin, Lopez-Onieva, Lourdes, Foster, Katie, Anjos-Afonso, Fernando, Lamrissi-Garcia, Isabelle, Serrano-Sanchez, Martin, Mitter, Richard, Ivanovic, Zoran, de Verneuil, Hubert, Gribben, John, Taussig, David, Rezvani, Hamid Reza, Mazurier, Frédéric, Bonnet, Dominique
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - physiology; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cells, Cultured; Endoplasmic Reticulum Stress - physiology; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humans; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Mice; Mitochondria - metabolism; Reactive Oxygen Species - metabolism
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2013.08.011

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-1α in the maintenance of murine HSCs; however, the role of HIF-2α is still unclear. Here, we show 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 stimulates endoplasmic reticulum (ER) stress and triggers apoptosis by activation of the unfolded-protein-response (UPR) pathway. HIF-2α deregulation also significantly decreased engraftment ability of human acute myeloid leukemia (AML) cells. Overall, our data demonstrate a key role for HIF-2α in the maintenance of human HSPCs and in the survival of primary AML cells. [Display omitted] •HIF-2α is essential for human HSPCs and acute myeloid leukemia survival•HIF-2α regulates mitochondrial ROS production•Silencing HIF-2α increases the endoplasmic reticulum stress induced by ROS Hif-2α knockdown impairs survival of human hematopoietic stem/progenitors and AML cells through increased ROS production and subsequent ER stress, which triggers apoptosis via activation of the unfolded protein response pathway.