Oxidative DNA damage in CD34(+) myelodysplastic cells is associated with intracellular redox changes and elevated plasma tumour necrosis factor-alpha concentration

Ineffective haemopoiesis in the myelodysplastic syndromes (MDS) is mediated, at least in part, by apoptosis, though the mechanisms of apoptotic induction are unclear. Tumour necrosis factor-alpha (TNF-alpha) promotes apoptosis via intracellular oxygen free radical production, oxidation of DNA and proteins, and is increasingly implicated in the pathogenesis of MDS. Using single-cell gel electrophoresis, we have identified oxidized pyrimidine nucleotides in the progenitor-enriched bone marrow CD34(+) compartment from MDS patients (P=0.039), which are absent in both CD34(-) MDS cells (P=0.53 and also CD34(+) cells from normal subjects (P=0.55). MDS CD34(+) blood cells also showed oxidized pyrimidine nucleotides compared with CD34(-) cells (P=0.029). Within normal subjects no differences were seen between CD34(+) and CD34(-) bone marrow cell compartments, CD34(+) bone marrow cell oxidized pyrimidines were strongly associated with elevated plasma TNF-alpha and low bone marrow mononuclear cell glutathione concentrations (5/6 patients) and the inverse relationship was also found (3/4 patients), This data implies a role for intracellular oxygen free radical production, perhaps mediated by TNF-alpha, in the pathogenesis of ineffective haemopoiesis in MDS and provides a rationale for the bone marrow stimulatory effects of antioxidants such as Amifostine in MDS.