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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3793-3801.
Prepublished online as a Blood First Edition Paper on January 17, 2008; DOI 10.1182/blood-2007-07-104042.
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NEOPLASIA
HO-1 underlies resistance of AML cells to TNF-induced apoptosis
Stuart A. Rushworth1, and
David J. MacEwan1
1 School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich, United Kingdom
In human monocytes, tumor necrosis factor (TNF) induces a proinflammatory response. In NF- B–inhibited monocytes, TNF stimulates cell death/apoptosis. In the present study, we analyzed the response of acute myeloid leukemia (AML) cells to TNF stimulation in conjunction with NF-B inhibition. In all AML-derived cells tested, NF-B–inhibited cells were resistant to TNF-induced apoptosis. Further investigation revealed that the cytoprotective gene heme oxygenase-1 (HO-1) was induced in NF-B–inhibited AML cells in response to TNF stimulation, and HO-1 was responsible for the resistance of AML cells to the cytotoxic actions of TNF. Moreover, after transfection with HO-1 siRNA, the resistance to TNF-induced cell death signals of AML cells was removed. The HO-1 promoter region contains antioxidant-response elements that can bind the transcription factor NF-E2–related factor 2 (Nrf2). We further demonstrated that Nrf2 was activated by TNF under NF-B–inhibited conditions, to play the major role in up-regulating HO-1 expression and ultimately the fate of AML cells. These results demonstrate a novel mechanism by which TNF-induced cell death is inhibited in AML cells through the induction of HO-1, via Nrf2 activation.
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