Tumor necrosis factor-α inhibits hTERT gene expression in human myeloid normal and leukemic cells

Telomerase catalytic subunit (hTERT) has been shown to play a critical role not only in telomere homeostasis but also in cellular survival, DNA repair, and genetic stability. In a previous study, we described that tumor necrosis factor-alpha (TNF alpha) induced in the leukemic KG1 cells a senescence state characterized by decreased hTERT activity followed by prolonged growth arrest, increased beta-galactosidase activity, telomere shortening, and major chromosomal instability. Interestingly, granulocyte-macrophage colony-stimulating factor (GM-CSF) abrogated all these events. In the present study, we show for the first time that TNF alpha acts by inhibiting the hTERT gene in both normal CD34(+) cells and fresh leukemic cells. Using KG1 cells as a representative cellular model, we show that TNF alpha induced sphingomyelin hydrolysis, ceramide production, and c-Jun N-terminal kinase (JNK) activation, all of which are critical components of TNF alpha signaling, resulting in hTERT gene inhibition. Moreover, we provide evidence that the protective effect of GMCSF is related to its capacity to interfere with both ceramide generation and ceramide signaling. Negative regulation of the hTERT gene may represent one mechanism by which TNF alpha interferes with normal hemopoiesis.