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Differentiation

Desferrioxamine induces leukemic cell differentiation potentially by hypoxia-inducible factor-1α that augments transcriptional activity of CCAAT/enhancer-binding protein-α

Leukemia volume 19, pages 1239–1247 (2005)Cite this article

Abstract

We reported recently that cobalt chloride-simulated hypoxia and mild hypoxia modified the differentiation of human acute myeloid leukemic (AML) cells, probably acting via a hypoxia-inducible factor-1 alpha (HIF-1α)-dependent mechanism. In this study, we investigated the effect of desferrioxamine (DFO), an iron chelator with ‘hypoxia-mimetic’ activity, on the differentiation of AML cells. The results showed that DFO at nontoxic concentrations induced the differentiation of AML cell lines NB4 and U937, as assessed by morphological criteria and differentiation-associated antigens. DFO-induced differentiation parallel to the rapid accumulation of HIF-1α protein in these two cell lines. Of importance, the transient transfection of HIF-1α cDNA induced U937 cells to develop the differentiation-related alterations such as growth arrest and increased CD11b expression. Furthermore, the inducible expression of chromosome translocation t(8;21)-generated leukemogenic AML1-ETO fusion gene attenuated DFO-induced differentiation of U937 cells with the decrease of CCAAT/enhancer-binding protein alpha (C/EBPα), a critical factor for granulocytic differentiation. Using immunoprecipitation and luciferase reporter assay, HIF-1α was also shown to interact physically with and to increase the transcriptional activity of C/EBPα. Taken together, these results provided novel evidence for a role of HIF-1α in AML cell differentiation, and suggested that C/EBPα might be a downstream effector for HIF-1α-mediated differentiation.

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Acknowledgements

This work was supported in part by National Key Program (973) for Basic Research of China (NO2002CB512806, NO2002CB512805), National Natural Science Foundation of China (30370592 and 90408009) and International Collaborative Items of Ministry of Science and Technology of China (2003DF000038). Grants from Science and Technology Commission of Shanghai, 100-Talent Program of Chinese Academy of Sciences and Jose-Carreras Foundation (00/14 to ML) should also be acknowledged.

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  1. Y Jiang, Z-H Xue and W-Z Shen: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Pathophysiology, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University (SSMU), Shanghai, China

    Y Jiang, Z-H Xue, W-Z Shen, K-M Du, H Yan, Y Yu, J-H Tong, Z Chen, Y Huang & G-Q Chen

  2. Division of Functional Genomics of Cancer, Health Science Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences-SSMU, Shanghai, China

    Z-G Peng, M-G Song & G-Q Chen

  3. Department of Medicine, University of Freiburg Medical Center, Freiburg, Germany

    M Lübbert

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Correspondence to G-Q Chen.

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Jiang, Y., Xue, ZH., Shen, WZ. et al. Desferrioxamine induces leukemic cell differentiation potentially by hypoxia-inducible factor-1α that augments transcriptional activity of CCAAT/enhancer-binding protein-α. Leukemia 19, 1239–1247 (2005). https://doi.org/10.1038/sj.leu.2403734

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