Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance
| Autor: | Lewis Allen, Juan Manuel Iglesias, Deniz Gezer, Tessa L. Holyoake, Juan Bautista Menendez-Gonzalez, Alasdair Ivens, Kamil R. Kranc, Alejandro Armesilla-Diaz, Dónal O'Carroll, Annemarie E.M. Post, Milica Vukovic, Katrin Schaak, Peter J. Ratcliffe, Theano I. Panagopoulou, Chithra Subramani, Arnaud Villacreces, Catarina Sepulveda, Amelie V. Guitart, Andrew J. Wood, Eoghan O'Duibhir, Fokion Glykofrydis, Chi Wai Eric So |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Myeloid
Cell Survival Immunology Molecular Sequence Data Chromosomal translocation Biology Small hairpin RNA 03 medical and health sciences Mice 0302 clinical medicine hemic and lymphatic diseases Cell Line Tumor medicine Basic Helix-Loop-Helix Transcription Factors Immunology and Allergy Animals Humans 030304 developmental biology Cell Proliferation Homeodomain Proteins 0303 health sciences Gene knockdown Base Sequence Gene Expression Regulation Leukemic Gene Expression Profiling Myeloid leukemia medicine.disease Hypoxia-Inducible Factor 1 alpha Subunit Cell Hypoxia 3. Good health Neoplasm Proteins Leukemia Disease Models Animal Leukemia Myeloid Acute medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research Disease Progression Neoplastic Stem Cells Bone marrow Stem cell CRISPR-Cas Systems Gene Deletion |
| Zdroj: | Vukovic, M, Guitart, A V, Sepulveda, C, Villacreces, A, O'Duibhir, E, Panagopoulou, T I, Ivens, A, Menendez-Gonzalez, J, Iglesias, J M, Allen, L, Glykofrydis, F, Subramani, C, Armesilla-Diaz, A, Post, A E M, Schaak, K, Gezer, D, So, C W E, Holyoake, T L, Wood, A, O'Carroll, D, Ratcliffe, P J & Kranc, K R 2015, ' Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance ', Journal of Experimental Medicine, vol. 212, no. 13, pp. 2223-2234 . https://doi.org/10.1084/jem.20150452 |
| ISSN: | 0022-1007 |
| DOI: | 10.1084/jem.20150452 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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