|Title||Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance.|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Vukovic M, Guitart A, Sepulveda C, Villacreces A, O'Duibhir E, Panagopoulou TI, Ivens A, Menendez-Gonzalez J, Iglesias JManuel, Allen L, Glykofrydis F, Subramani C, Armesilla-Diaz A, Post AEM, Schaak K, Gezer D, So CWai Eric, Holyoake TL, Wood A, O'Carroll D, Ratcliffe PJ, Kranc KR|
|Journal||J Exp Med|
|Date Published||2015 Dec 14|
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.
|Alternate Journal||J. Exp. Med.|