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.
Peddie
C M
CM
Department of Molecular and Cellular Pathology, Ninewells Hospital and Medical School, Dundee.
Wolf
C R
CR
McLellan
L I
LI
Collins
A R
AR
Bowen
D T
DT
D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34; D017209:Apoptosis; D004249:DNA Damage; D004797:Enzyme-Linked Immunosorbent Assay; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D011741:Pyrimidine Nucleosides / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D018952:Antigens, CD34; D011741:Pyrimidine Nucleosides; D013438:Sulfhydryl Compounds; D014409:Tumor Necrosis Factor-alpha; D005978:Glutathione