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

BACKGROUND

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.

CONCLUSIONS

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).