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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 publication

DOI

10.1084/jem.20150452

Type

Journal article

Journal

J Exp Med

Publication Date

14/12/2015

Volume

212

Pages

2223 - 2234

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, Myeloid Ecotropic Viral Integration Site 1 Protein, Neoplasm Proteins, Neoplastic Stem Cells