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Project ID: 224783
Funded under: FP7-PEOPLE
Country: Italy

Hypoxia and leukaemia

Hypoxia or insufficient oxygen triggers the development of solid tumours. Studies by an EU-funded project have demonstrated that hypoxia-inducible factors (HIFs) play a major role in the progression of leukaemia.
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.

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