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

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.

This work was supported by grants from the INSERM, the Fondation de France, and the Association pour la Recherche contre le Cancer.

Institut National de la Santé et de la Recherche Médicale (INSERM) U563, Centre de Physiopathologie de Toulouse Purpan, Place du Docteur Baylac, Toulouse, 31059, France

Odile Beyne-Rauzy, Christian Recher, Nicole Dastugue, Cécile Demur, Guy Laurent & Véronique Mansat-De Mas

Service d'Hématologie, Centre Hospitalier Universitaire Purpan, Place du Docteur Baylac, Toulouse, 31059, France

Laboratoire d'Hématologie, Centre Hospitalier Universitaire Purpan, Place du Docteur Baylac, Toulouse, 31059, France

CEA-DSV/DRR/LRO, 18 Route du Panorama, 92265 Fontenay aux roses cedex, France

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