Tumor Necrosis Factor Alpha Inhibits Telomerase and Induces Senescence in Acute Myeloid Leukemia Cells.

Tumor necrosis factor alpha (TNFα) is a multifunctional cytokine, which is overproduced in a series of hematological diseases, including acute myeloblastic leukemia (AML) and myelodysplasia (MDS). Apoptotic cell killing has been the most frequently documented cellular effect of TNFα in AML cells. Much little is known about TNFα effect in AML cells, which display an intrinsic defect in their apoptotic machinery. In this study, we describe that prolonged exposure to TNFα, but not Fas, resulted in senescence in the immature CD34⁺ CD38⁻ KG1 cell line. Indeed, TNFα-treated KG1 cells displayed growth arrest, increased senescence-associated β-galactosidase activity, telomere shortening and additional chromosomal abberations. In these cells, as well as in fresh AML cells, treatment with TNFα resulted in decreased hTERT gene trancription and hTERT activity. Moreover, we found that ceramide production and JNK activation were critical signaling components in TNFα-induced hTERT gene inhibition. GM-CSF stimulation inhibited ceramide production, JNK activation, hTERT inhibition, and senescence markers induction. To conclude, our study suggests that, at least in some AML cells, TNFα is a regulator of hTERT with important functional consequences in terms of growth capacity and genetic stability. Moreover, the pro-senescent effect of TNFα is efficiently counter-regulated by stimulatory cytokines such as GM-CSF.