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

2005; Elsevier BV; Volume: 106; Issue: 9 Linguagem: Inglês

10.1182/blood-2005-04-1386

1528-0020

Odile Beyne-Rauzy, Naïs Prade-Houdellier, Cécile Demur, Christian Récher, J.-E. Ayel, Guy Laurent, Véronique Mansat‐De Mas,

Immunotherapy and Immune Responses

Abstract 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-×α (TNF×α) induced in the leukemic KG1 cells a senescence state characterized by decreased hTERT activity followed by prolonged growth arrest, increased× β-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×α 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×α induced sphingomyelin hydrolysis, ceramide production, and c-Jun N-terminal kinase (JNK) activation, all of which are critical components of TNF×α signaling, resulting in hTERT gene inhibition. Moreover, we provide evidence that the protective effect of GM-CSF 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×α interferes with normal hemopoiesis.