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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

The Journal of experimental medicine

Publication Date

07/12/2015

Volume

212

Pages

2223 - 2234

Addresses

MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, Scotland, UK.

Keywords

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