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Keywords:

  • myelodysplasia;
  • oxidative;
  • TNF-α;
  • apoptosis;
  • glutathione

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-α (TNF-α) 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-α 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-α, 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.