Vukovic, M. et al. (2015) Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance. Journal of Experimental Medicine, 212(13), pp. 2223-2234. (doi: 10.1084/jem.20150452) (PMID:26642852) (PMCID:PMC4689165)
|
Text
114717.pdf - Published Version Available under License Creative Commons Attribution Non-commercial Share Alike. 2MB |
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
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Gezer, Dr Deniz and Holyoake, Professor Tessa |
| Authors: | 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., and Kranc, K. R. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Journal of Experimental Medicine |
| Publisher: | Rockefeller University Press |
| ISSN: | 0022-1007 |
| ISSN (Online): | 1540-9538 |
| Copyright Holders: | Copyright © 2015 Vukovic et al. |
| First Published: | First published in Journal of Experimental Medicine 212(13):2223-2234 |
| Publisher Policy: | Reproduced under a Creative Commons License |
University Staff: Request a correction | Enlighten Editors: Update this record
Altmetric
Altmetric