Genes that act as brakes to stop the development of an aggressive form of leukaemia have been identified by researchers. Their findings offer fresh insights into how to tackle the disease and could lead to new therapies that prevent relapses.
Scientists have found that two molecules – Hif-1alpha and Hif-2alpha – work together to stop the formation of leukemic stem cells in an aggressive type of blood cancer called Acute Myeloid Leukaemia (AML).
The cancer occurs when production of new blood cells by the bone marrow goes awry. This leads to the formation of leukemic stem cells, which fuel the disease and provide a constant flow of abnormal leukaemia cells.
The University of Edinburgh study shows that blocking Hif-2alpha – or both Hif-1alpha and Hif-2alpha – accelerates the development of leukaemia. The findings are surprising because previous research had suggested that blocking Hif-1alpha or Hif-2alpha may stop leukaemia progression.
The work was carried out at the University’s MRC Centre for Regenerative Medicine and the Edinburgh Cancer Research Centre.
Researchers say that their new results suggest that therapies designed to block these molecules may have no impact or could even worsen disease. Conversely, designing new therapies that promote the activity of Hif-1alpha and Hif-2alpha could help to treat AML or stop the disease from recurring after chemotherapy.
Around 2,500 people are diagnosed with AML in the UK each year. Chemotherapy drugs can help to eliminate leukaemia cells but have no effect on leukemic stem cells that cause the disease. This means the disease sometimes relapses.
Professor Kamil R Kranc, Cancer Research UK Senior Fellow at the MRC Centre for Regenerative Medicine, who led the study, said:
Our discovery that Hif-1alpha and Hif-2alpha molecules act together to stop leukaemia development is a major milestone in our efforts to combat leukaemia. We now intend to harness this knowledge to develop curative therapies that eliminate leukaemic stem cells, which are the underlying cause of AML.
Dr Milica Vukovic, first author of the study, said:
Leukaemia is an umbrella term for a vast number of very complicated and different diseases. Given our findings implicating Hif-1alpha and Hif-2alpha as tumour suppressors in AML, it would be very interesting to investigate their roles in other leukaemias.
Vukovic M, Guitart AV, Sepulveda C, Villacreces A, O'Duibhir E, Panagopoulou TI, Ivens A, Menendez-Gonzalez J, Iglesias JM, Allen L, 1 Fokion Glykofrydis G, Subramani C, Armesilla-Diaz A, Post AEM, Schaak K, Gezer D, So CWE, Holyoake TL, Wood A, Dónal O'Carroll D, Ratcliffe PJ, Kranc KR. 2015. Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance. Journal of Experimental Medicine, volume 212, number 13. Published online 7 December 2015.
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 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-1α and Hif-2α synergize to suppress the development of AML, they are not required for LSC maintenance.