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

作者：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 Frederic^*; Bonnet Dominique

来源：Cell Stem Cell, 2013, 13(5): 549-563.

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-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.

• 出版日期2013-11-7