title: Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance.
abstract: Leukemogenesis occurs under hypoxic conditions within the bone marrow (BM). Knockdown of key mediators of cellular responses to hypoxia with shRNA, namely hypoxia-inducible factor-1α (HIF-1α) or HIF-2α, in human acute myeloid leukemia (AML) samples results in their apoptosis and inability to engraft, implicating HIF-1α or HIF-2α as therapeutic targets. However, genetic deletion of Hif-1α has no effect on mouse AML maintenance and may accelerate disease development. Here, we report the impact of conditional genetic deletion of Hif-2α or both Hif-1α and Hif-2α at different stages of leukemogenesis in mice. Deletion of Hif-2α accelerates development of leukemic stem cells (LSCs) and shortens AML latency initiated by Mll-AF9 and its downstream effectors Meis1 and Hoxa9. Notably, the accelerated initiation of AML caused by Hif-2α deletion is further potentiated by Hif-1α codeletion. However, established LSCs lacking Hif-2α or both Hif-1α and Hif-2α propagate AML with the same latency as wild-type LSCs. Furthermore, pharmacological inhibition of the HIF pathway or HIF-2α knockout using the lentiviral CRISPR-Cas9 system in human established leukemic cells with MLL-AF9 translocation have no impact on their functions. We therefore conclude that although Hif-1α and Hif-2α synergize to suppress the development of AML, they are not required for LSC maintenance.
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Milica
authors.initials: M
authors.lastname: Vukovic
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Amelie V
authors.initials: AV
authors.lastname: Guitart
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Catarina
authors.initials: C
authors.lastname: Sepulveda
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Villacreces
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Eoghan
authors.initials: E
authors.lastname: O'Duibhir
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Theano I
authors.initials: TI
authors.lastname: Panagopoulou
authors.affiliation: Centre for Infection, Immunity, and Evolution, King's Buildings, University of Edinburgh, Edinburgh EH9 3FL, Scotland, UK.
authors.forename: Alasdair
authors.initials: A
authors.lastname: Ivens
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Juan
authors.initials: J
authors.lastname: Menendez-Gonzalez
authors.affiliation: Synpromics Limited, Edinburgh EH16 4UX, Scotland, UK.
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Iglesias
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Lewis
authors.initials: L
authors.lastname: Allen
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Fokion
authors.initials: F
authors.lastname: Glykofrydis
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Chithra
authors.initials: C
authors.lastname: Subramani
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Armesilla-Diaz
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Annemarie E M
authors.initials: AE
authors.lastname: Post
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schaak
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, Scotland, UK Klinik fuer Haematologie, Onkologie und Stammzelltransplantation, Universitaetsklinikum Aachen, 52074 Aachen, Germany Paul O'Gorman Leukaemia Research Centre, University of Glasgow, Glasgow G120 ZD, Scotland, UK.
authors.forename: Deniz
authors.initials: D
authors.lastname: Gezer
authors.affiliation: Department of Haematological Medicine, King's College London, London SE5 9RS, England, UK.
authors.forename: Chi Wai Eric
authors.initials: CW
authors.lastname: So
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, University of Glasgow, Glasgow G120 ZD, Scotland, UK.
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, Scotland, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wood
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, Scotland, UK European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, 00015 Monterotondo Scalo, Italy.
authors.forename: Dónal
authors.initials: D
authors.lastname: O'Carroll
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7BN, England, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, Scotland, UK Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, Scotland, UK kamil.kranc@ed.ac.uk.
authors.forename: Kamil R
authors.initials: KR
authors.lastname: Kranc
mesh_terms: D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D064113:CRISPR-Cas Systems / Q000235:genetics; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004195:Disease Models, Animal; D018450:Disease Progression; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008969:Molecular Sequence Data; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; C097899:homeobox protein HOXA9