Hypoxia increases HIF-1α expression and constitutive cytokine release by primary human acute myeloid leukaemia cells.

INTRODUCTION: Low oxygen tension is able to modulate the expression of several genes involved in physiological and pathological processes. A major regulator of gene expression is the heterodimeric transcription factor hypoxia inducible factor-1 (HIF-1), which also regulates angiogenesis-related genes, including the protein expression of angioregulatory cytokines. Angiogenesis has been shown to play a role in haematological disorders, and low oxygen tension might thereby influence leukaemogenesis and chemosensitivity in human acute myeloid leukaemia (AML). METHODS: We examined the effect of a hypoxic environment (1% O(2)) on in vitro-cultured, primary human AML cells with regard to HIF-1α expression, colony formation and cytokine release. RESULTS: Our study demonstrated that hypoxic culture conditions increased HIF-1α expression in primary AML cells for a majority of the investigated patients when compared to culture at atmospheric (21%) oxygen tension. Hypoxia also increased the release of vascular endothelial growth factor (VEGF), osteopontin, as well as several CCL- (CCL3/4/5/7/8) and CXCL-chemokines (CXCL1 and proangiogenic CXCL8) by AML cells. The constitutive release of antiangiogenic CXCL9-11 was not altered by the low oxygen tension. The wide variation between patients as regards the release of the various cytokines persisted during hypoxia. CONCLUSION: Culture of primary AML cells under low oxygen tension induces HIF-1α expression and increases the release of several cytokines, including proangiogenic mediators, compared to culture at ambient 21% O(2).