Open Access

ARTICLE

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

Kimberley Joanne Hatfield¹, Siv Lise Bedringsaas², Anita Ryningen³, Bjørn Tore Gjertsen^1,2, Øystein Bruserud^1,2

1 Department of Medicine, Division of Haematology, Haukeland University Hospital, Bergen, Norway
2 Section for Haematology, Institute of Medicine, University of Bergen, Norway
3 The Blood Bank, Haukeland University Hospital, Bergen, Norway

* Corresponding Author: Ø. Bruserud,

European Cytokine Network 2010, 21(3), 154-164. https://doi.org/10.1684/ecn.2010.0204

Accepted 01 July 2010;

Abstract

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 transcrip tion 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% O₂) 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 pri mary 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% O₂.

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