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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References
Semenza GL . Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003; 3: 721–732.
Fukuda R, Hirota K, Fan F, Jung YD, Ellis LM, Semenza GL . Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J Biol Chem 2002; 277: 38205–38211.
Berra E, Benizri E, Ginouves A, Volmat V, Roux D, Pouyssegur J . HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J 2003; 22: 4082–4090.
Chan DA, Sutphin PD, Denko NC, Giaccia AJ . Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1α. J Biol Chem 2002; 277: 40112–40117.
Harris AL . Hypoxia – a key regulatory factor in tumour growth. Nat Rev Cancer 2002; 2: 38–47.
Hon WC, Wilson MI, Harlos K, Claridge TD, Schofield CJ, Pugh CW et al. Structural basis for the recognition of hydroxyproline in HIF-1 alpha by Pvhl. Nature 2002; 417: 975–978.
Ivanovic Z, Sbarba DP, Trimoreau F, Faucher JL, Praloran V . Primitive human HPCs are better maintained and expanded at 1% oxygen than at 20%. Transfusion 2000; 40: 1482–1488.
Desplat V, Faucher JL, Mahon FX, Sbarba DP, Praloran V, Ivanovic Z . Hypoxia modifies proliferation and differentiation of CD34+ CML cells. Stem Cells 2002; 20: 347–354.
Huang Y, Du KM, Xue ZH, Yan H, Li D, Liu W et al. Cobalt chloride and low oxygen tension trigger differentiation of AML cells: possible mediation of hypoxia-inducible factor-1α. Leukemia 2003; 17: 2065–2073.
Lanotte M, Martin-Thouvenin V, Najman S, Balerini P, Valensi F, Berger R . NB4, a maturation inducible cell line with t(15;17) marker isolated from a human acute promyelocytic leukemia (M3). Blood 1991; 77: 1081–1086.
Fliegauf M, Stock M, Berg T, Lübbert M . Williams–Beuren syndrome critical region-5/non-T-cell activation linker: a novel target gene of AML1/ETO. Oncogene 2004; 23: 9070–9081.
Lee P, Mohammed N, Marshall L, Abeysinghe RD, Hider RC, Porter JB et al. Intravenous infusion pharmacokinetics of desferrioxamine in thalassaemic patients. Drug Metab Dispos 1993; 21: 640–644.
Zhao KW, Li X, Zhao Q, Huang Y, Li D, Peng ZG et al. Protein kinase Cδ mediates retinoic acid and phorbol myristate acetate-induced PLSCR1 gene expression: its role in leukemic cell differentiation. Blood 2004; 104: 3731–3738.
Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y . A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA 1997; 94: 4273–4278.
Smith LT, Hohaus S, Gonzales DA, Dziennis SE, Tenen DG . PU.1 (Spi-1) and C/EBP alpha regulate the granulocyte colony-stimulating factor receptor promoter in myeloid cells. Blood 1996; 88: 1234–1247.
Nordeen SK . Luciferase reporter gene vectors for analysis of promoters and enhancers. BioTechniques 1988; 6: 454–457.
Peterson LF, Zhang DE . The 8;21 translocation in leukemogenesis. Oncogene 2004; 23: 4255–4262.
Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G et al. AML1-ETO downregulates the granulocytic differentiation factor C/EBPα in t(8;21) myeloid leukemia. Nat Med 2001; 4: 407–408.
Westendorf JJ, Yamamoto CM, Lenny N, Downing JR, Selsted ME, Hiebert SW . The t(8;21) fusion product, AML-1-ETO, associates with C/EBP-1α, inhibits C/EBP-1α-dependent transcription, and blocks granulocytic differentiation. Mol Cell Biol 1998; 18: 322–333.
Huang LE, Bunn HF . Hypoxia-inducible factor and its biomedical relevance. J Biol Chem 2003; 278: 19575–19578.
Uchida T, Rossignol F, Matthay MA, Mounier R, Couette S, Clottes E et al. Prolonged hypoxia differentially regulates HIF-1alpha and HIF-2alpha expression in lung epithelial cells: implication of natural antisense HIF-1alpha. J Biol Chem 2004; 279: 14871–14878.
Asou H, Tashiro S, Hamamoto K, Otsuji A, Kita K, Kamada N . Establishment of a human AML cell line (Kasumi-1) with 8;21 chromosome translocation. Blood 1991; 77: 2031–2036.
Ahn MY, Huang G, Bae SC, Wee HJ, Kim WY, Ito Y . Negative regulation of granulocytic differentiation in the myeloid precursor cell line 32Dcl3 by ear-2, a mammalian homolog of Drosophila seven-up, and a chimeric leukemogenic gene, AML1/ETO. Proc Natl Acad Sci USA 1998; 95: 1812–1817.
Kohzaki H, Ito K, Huang G, Wee HJ, Murakami Y, Ito Y . Block of granulocytic differentiation of 32Dcl3 cells by AML1/ETO(MTG8) but not by highly expressed Bcl-2. Oncogene 1999; 18: 4055–4062.
Burel SA, Harakawa N, Zhou L, Pabst T, Tenen DG, Zhang DE . Dichotomy of AML1-ETO functions: growth arrest versus block of differentiation. Mol Cell Biol 2001; 21: 5577–5590.
Tonks A, Tonks AJ, Pearn L, Pearce L, Hoy T, Couzens S et al. Expression of AML1-ETO in human myelomonocytic cells selectively inhibits granulocytic differentiation and promotes their self-renewal. Leukemia 2004; 18: 1238–1245.
Heidenreich O, Krauter J, Riehle H, Hadwiger P, John M, Heil G et al. AML1/MTG8 oncogene suppression by small interfering RNAs supports myeloid differentiation of t(8;21)-positive leukemic cells. Blood 2003; 101: 3157–3163.
Schwieger M, Lohler J, Fischer M, Herwig U, Tenen DG, Stocking C . A dominant-negative mutant of C/EBPα, associated with acute myeloid leukemias, inhibits differentiation of myeloid and erythroid progenitors of man but not mouse. Blood 2004; 103: 2744–2752.
Truong BT, Lee YJ, Lodie TA, Park DJ, Perrotti D, Watanabe N et al. CCAAT/enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia. Blood 2003; 101: 1141–1148.
Radomska HS, Huettner CS, Zhang P, Cheng T, Scadden DT, Tenen DG . CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol Cell Biol 1998; 18: 4301–4314.
Nerlov C, McNagny KM, Doderlein G, Kowenz-Leutz E, Graf T . Distinct C/EBP functions are required for eosinophil lineage commitment and maturation. Genes Dev 1998; 12: 2413–2423.
Gombart AF, Hofmann WK, Kawano S, Takeuchi S, Krug U, Kwok SH et al. Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias. Blood 2002; 99: 1332–1340.
Tenen DG . Abnormalities of the CEBP alpha transcription factor: a major target in acute myeloid leukemia. Leukemia 2001; 15: 688–689.
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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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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DOI: https://doi.org/10.1038/sj.leu.2403734
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