Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance

Milica Vukovic, Amelie V Guitart, Catarina Sepulveda, Arnaud Villacreces, Eoghan O'Duibhir, Theano I Panagopoulou, Alasdair Ivens, Juan Menendez-Gonzalez, Juan Manuel Iglesias, Lewis Allen, Fokion Glykofrydis, Chithra Subramani, Alejandro Armesilla-Diaz, Annemarie E M Post, Katrin Schaak, Deniz Gezer, Chi Wai Eric So, Tessa L Holyoake, Andrew Wood, Dónal O'CarrollPeter J Ratcliffe, Kamil R Kranc

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2223-2234
Number of pages12
JournalJournal of Experimental Medicine
Volume212
Issue number13
Early online date7 Dec 2015
DOIs
Publication statusPublished - 14 Dec 2015

Keywords

  • Animals
  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors
  • CRISPR-Cas Systems
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Disease Models, Animal
  • Disease Progression
  • Gene Deletion
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic
  • Homeodomain Proteins
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Leukemia, Myeloid, Acute
  • Mice
  • Molecular Sequence Data
  • Neoplasm Proteins
  • Neoplastic Stem Cells

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