| Autor: |
Vukovic, Milica, Guitart, Amelie V., Sepulveda, Catarina, Villacreces, Arnaud, O'Duibhir, Eoghan, Panagopoulou, Theano I., Ivens, Alasdair, Menendez-Gonzalez, Juan, Iglesias, Juan Manuel, Allen, Lewis, Glykofrydis, Fokion, Subramani, Chithra, Armesilla-Diaz, Alejandro, Post, Annemarie E.M., Schaak, Katrin, Gezer, Deniz, So, Chi Wai Eric, Holyoake, Tessa L., Wood, Andrew, O'Carroll, Dónal, Ratcliffe, Peter J., Kranc, Kamil R. |
| Zdroj: |
The Journal of Experimental Medicine; December 2015, Vol. 212 Issue: 13 p2223-2234, 12p |
| Abstrakt: |
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: |
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