title: HIF-1α can act as a tumor suppressor gene in murine acute myeloid leukemia.
abstract: Self-renewal of hematopoietic stem cells (HSCs) and leukemia-initiating cells (LICs) has been proposed to be influenced by low oxygen tension (hypoxia). This signaling, related to the cellular localization inside the bone marrow niche and/or influenced by extrinsic factors, promotes the stabilization of hypoxia-inducible factors (HIFs). Whether HIF-1α can be used as a therapeutic target in the treatment of myeloid malignancies remains unknown. We have used 3 different murine models to investigate the role of HIF-1α in acute myeloid leukemia (AML) initiation/progression and self-renewal of LICs. Unexpectedly, we failed to observe a delay or prevention of disease development from hematopoietic cells lacking Hif-1α. In contrast, deletion of Hif-1α resulted in faster development of the disease and an enhanced leukemia phenotype in some of the investigated models. Our results therefore warrant reconsideration of the role of HIF-1α and, as a consequence, question its generic therapeutic usefulness in AML.
authors.affiliation: Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund, Sweden;
authors.forename: Talia
authors.initials: T
authors.lastname: Velasco-Hernandez
authors.affiliation: Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund, Sweden;
authors.forename: Axel
authors.initials: A
authors.lastname: Hyrenius-Wittsten
authors.affiliation: Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund, Sweden;
authors.forename: Matilda
authors.initials: M
authors.lastname: Rehn
authors.affiliation: Department of Immunology, Lund University, Lund, Sweden; and.
authors.forename: David
authors.initials: D
authors.lastname: Bryder
authors.affiliation: Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund, Sweden; Department of Hematology, Skanes University Hospital, Lund, Sweden.
authors.forename: Jörg
authors.initials: J
authors.lastname: Cammenga
mesh_terms: D000818:Animals; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D025521:Tumor Suppressor Proteins