Hypoxia inducible factor prolyl hydroxylase inhibition compromises development and progression of acute myeloid leukaemia
Acute myeloid leukaemia (AML) is a largely incurable haematological disease, for which new efficient therapeutic strategies are urgently needed. While leukaemogenesis occurs under hypoxic conditions of the bone marrow, the therapeutic tractability of the hypoxia inducible factor (HIF) system in AML is elusive. Given that inactivation of HIF-1a and HIF-2a promotes leukaemic transformation, a possible therapeutic strategy for AML treatment is to constitutively stabilise HIF- a proteins. This can be achieved by targeting the HIF-prolyl hydroxylases (PHDs), the catalysis of which promotes HIF-1a and HIF-2a degradation. Here, we demonstrate that genetic inactivation of Phd1 or Phd2 compromises initiation and progression of AML, without impacting normal haematopoiesis, thus implying the immense therapeutic potential of targeting PHDs in AML. To pharmacologically inactivate PHDs, we employed clinical grade PHD inhibitors as well as a new selective PHD inhibitor (IOX5), which stabilises HIF-a through a novel mechanism of action. Pharmacological PHD inhibition compromises AML cells in a HIF-a dependent manner to disable pro-leukaemogenic pathways in AML cells, re-program their metabolism, and induce cell death, at least in part via pro-apoptotic BNIP3. Importantly, concurrent inhibition of anti-apoptotic BCL-2 by clinically used Venetoclax potentiates the anti-leukaemic effect of PHD inhibition. Thus PHD inhibition with consequent HIF-a stabilisation is a promising new non-toxic strategy for AML treatment. Overall design: Comparative gene expression profiling analysis of RNA-seq data for iMLL-AF9 preleukaemic cells treated with PHD2 inhibitor.