Abstract / Description of output
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 language | English |
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Pages (from-to) | 2223-2234 |
Number of pages | 12 |
Journal | Journal of Experimental Medicine |
Volume | 212 |
Issue number | 13 |
Early online date | 7 Dec 2015 |
DOIs | |
Publication status | Published - 14 Dec 2015 |
Keywords / Materials (for Non-textual outputs)
- 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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Andrew Wood
- Deanery of Molecular, Genetic and Population Health Sciences - Reader
- MRC Human Genetics Unit
- Edinburgh Haematopoiesis Network
Person: Academic: Research Active