Hypoxia and leukaemia
Human solid tumours are less oxygenated than the normal tissues from which they arise. This tumour hypoxia leads to resistance to radiotherapy, anti-cancer chemotherapy and increased tumour metastases. HIFs are transcription factors (TFs) that respond to decreases in available oxygen in the cellular environment. HIFs are often up-regulated in solid tumours because of intra–tumour hypoxia. In solid tumours, HIF activation triggers the induction of anaerobic metabolism, cell migration and neo-angiogenesis, and promotes maintenance of cancer stem cells. In leukaemia and lymphoma, the role of HIFs is less studied. Recent work has shown that HIF-1alpha is up-regulated in certain types of leukaemia, where it may regulate neo-angiogenic processes. HIF-1alpha is overexpressed in leukaemia stem cells (in lymphoma and acute myeloid leukaemia), where it regulates stem cell maintenance. high concentrations of the pro-angiogenic vascular endothelial growth factor (VEGF) are commonly found in the bone marrow of leukaemia patients. The project 'Role of angiogenesis in leukemia' (LEUKEMIA AND VEGF) investigated the cross-talk of activation of the TF HIF-1alpha, high VEGF expression and bone marrow neo-angiogenesis in leukaemia. researchers found that the oncogenic fusion protein of acute pro-myelocytic leukaemia (APL) acts as a HIF-transcriptional co-activator, thus leading to the up-regulation of HIF-dependent genes. In silico analysis of gene expression data from APL patients confirmed that activation of HIF-dependent pathways is relevant to the pathophysiology of APL. cell model experiments showed that HIF-1alpha induces cell migration, up-regulates VEGF, promotes neo-angiogenesis and regulates maintenance of colony-forming leukaemic cells. Experiments on a mouse model confirmed that inhibition of HIF-1alpha slows leukaemia progression by inhibiting cell migration, neo-angiogenesis and colony formation. project studies utilised HIF inhibitors that are currently used in clinical trials for solid tumours. Project results can be applied immediately to treatments for leukaemia patients.
