Tumor necrosis factor alpha induces senescence and chromosomal instability in human leukemic cells

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Abstract
Previous studies have documented that Tumor necrosis factor alpha (TNFα) is a potent negative regulator of normal hematopoiesis. However, the mechanism by which TNFα acts at the cellular level is not totally understood. Although apoptotic cell killing appears to be the most common cellular effect of TNFα, other studies suggest that this cytokine may elicit other cellular responses such as prolonged growth inhibition. In this context, we have investigated whether TNFα may induce senescence in hematopoietic cells, which display intrinsic defect in the apoptotic machinery. The present study described that, in the leukemic KG1 cells, TNFα induced no apoptosis but a senescence state characterized by prolonged growth arrest, increased β-galactosidase activity, p21WAF-1 induction, decreased telomerase activity, telomeric disturbances (shortening, losses, fusions), and additional chromosomal aberrations. Telomerase inhibition correlated with reduced levels of hTERT transcripts. GM-CSF prevented TNFα effects and allowed leukemic cells to recover growth capacity. Finally, our study shows for the first time that, at least in some hematopoietic cells, TNFα may induce senescence with important functional consequences, including sustained growth inhibition and genetic instability, and that this cellular response is efficiently regulated by hematopoietic growth factors.

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