OXIDATIVE DNA-DAMAGE IN CD34(-NECROSIS-FACTOR-ALPHA CONCENTRATION() MYELODYSPLASTIC CELLS IS ASSOCIATED WITH INTRACELLULAR REDOX CHANGES AND ELEVATED PLASMA TUMOR)

Ineffective haemopoiesis in the myelodysplastic syndromes (MDS) is med iated, at least in part, by apoptosis, though the mechanisms of apopto tic induction are unclear. Tumour necrosis factor-alpha (TNF-alpha) pr omotes apoptosis via intracellular oxygen free radical production, oxi dation of DNA and proteins, and is increasingly implicated in the path ogenesis of MDS. Using single-cell gel electrophoresis, we have identi fied oxidized pyrimidine nucleotides in the progenitor-enriched bone m arrow CD34(+) compartment from MDS patients (P=0.039), which are absen t 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 pyrim idine nucleotides compared with CD34(-) cells (P=0.029). Within normal subjects no differences were seen between CD34(+) and CD34(-) bone ma rrow cell compartments, CD34(+) bone marrow cell oxidized pyrimidines were strongly associated with elevated plasma TNF-alpha and low bone m arrow mononuclear cell glutathione concentrations (5/6 patients) and t he inverse relationship was also found (3/4 patients), This data impli es a role for intracellular oxygen free radical production, perhaps me diated by TNF-alpha, in the pathogenesis of ineffective haemopoiesis i n MDS and provides a rationale for the bone marrow stimulatory effects of antioxidants such as Amifostine in MDS.