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

TY - JOUR

T1 - Oxidative DNA damage in CD34+ myelodysplastic cells is associated with intracellular redox changes and elevated plasma tumour necrosis factor-α concentration

AU - Peddie, Clare M.

AU - Wolf, C. Roland

AU - Mclellan, Lesley I.

AU - Collins, Andrew R.

AU - Bowen, David T.

PY - 1997/12

Y1 - 1997/12

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Glutathione

KW - Myelodysplasia

KW - Oxidative

KW - TNF-α

UR - https://www.scopus.com/pages/publications/0030664927

U2 - 10.1046/j.1365-2141.1997.4373247.x

DO - 10.1046/j.1365-2141.1997.4373247.x

M3 - Article

C2 - 9401076

AN - SCOPUS:0030664927

SN - 0007-1048

VL - 99

SP - 625

EP - 631

JO - British Journal of Haematology

JF - British Journal of Haematology

IS - 3

ER -