Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance

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-1 alpha (HIF-1 alpha) or HIF-2 alpha, in human acute myeloid leukemia (AML) samples results in their apoptosis and inability to engraft, implicating HIF-1 alpha or HIF-2 alpha as therapeutic targets. However, genetic deletion of Hif-1 alpha has no effect on mouse AML maintenance and may accelerate disease development. Here, we report the impact of conditional genetic deletion of Hif-2 alpha or both Hif-1 alpha and Hif-2 alpha at different stages of leukemogenesis in mice. Deletion of Hif-2 alpha 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-2 alpha deletion is further potentiated by Hif-1 alpha codeletion. However, established LSCs lacking Hif-2 alpha or both Hif-1 alpha and Hif-2 alpha propagate AML with the same latency as wild-type LSCs. Furthermore, pharmacological inhibition of the HIF pathway or HIF-2 alpha knockout using the lentiviral CRI SPR-Cas9 system in human established leukemic cells with MLL-AF9 translocation have no impact on their functions. We therefore conclude that although Hif-1 alpha and Hif-2 alpha synergize to suppress the development of AML, they are not required for LSC maintenance.