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

Clare M. Peddie, C. Roland Wolf, Lesley I. Mclellan, Andrew R. Collins, David T. Bowen

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    97 Citations (Scopus)

    Abstract

    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 (TNP-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.

    Original languageEnglish
    Pages (from-to)625-631
    Number of pages7
    JournalBritish Journal of Haematology
    Volume99
    Issue number3
    DOIs
    Publication statusPublished - Dec 1997

    Keywords

    • Apoptosis
    • Glutathione
    • Myelodysplasia
    • Oxidative
    • TNF-α

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