| First Author | Vukovic M | Year | 2015 |
| Journal | J Exp Med | Volume | 212 |
| Issue | 13 | Pages | 2223-34 |
| PubMed ID | 26642852 | Mgi Jnum | J:229015 |
| Mgi Id | MGI:5750239 | Doi | 10.1084/jem.20150452 |
| Citation | Vukovic M, et al. (2015) Hif-1alpha and Hif-2alpha synergize to suppress AML development but are dispensable for disease maintenance. J Exp Med 212(13):2223-34 |
| abstractText | 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-1alpha (HIF-1alpha) or HIF-2alpha, in human acute myeloid leukemia (AML) samples results in their apoptosis and inability to engraft, implicating HIF-1alpha or HIF-2alpha as therapeutic targets. However, genetic deletion of Hif-1alpha has no effect on mouse AML maintenance and may accelerate disease development. Here, we report the impact of conditional genetic deletion of Hif-2alpha or both Hif-1alpha and Hif-2alpha at different stages of leukemogenesis in mice. Deletion of Hif-2alpha 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-2alpha deletion is further potentiated by Hif-1alpha codeletion. However, established LSCs lacking Hif-2alpha or both Hif-1alpha and Hif-2alpha propagate AML with the same latency as wild-type LSCs. Furthermore, pharmacological inhibition of the HIF pathway or HIF-2alpha 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-1alpha and Hif-2alpha synergize to suppress the development of AML, they are not required for LSC maintenance. |
