Myelodysplastic Syndromes Myelodysplastic syndromes: recent advances

Etiology of myelodysplastic syndromes The models for the development of sporadic MDS suggest the role of cumulative environmental exposures in genetically predisposed individuals. There is increasing evidence for a complex genetic predisposition to MDS involving naturally occurring DNA polymorphisms in genes that mediate DNA repair and metabolize environmental carcinogens.3 Large epidemiologic studies link MDS to radiation, smoking, occupational exposure to pesticides, organic chemicals and heavy metals.6-8 The mechanisms responsible for the initiation of MDS include nuclear and mitochondrial DNA mutations by carcinogen-DNA adducts and formation of oxygenfree radicals (OFRs), defective DNA repair resulting in genomic instability and dysregulation of immune surveillance. This last probably synergizes with genomic mutations to promote leukemogenesis. An emerging model of carcinogenic effects mediated via both genotoxic and non-genotoxic mechanisms is furnished by exposure to benzene. Benzene metabolites form DNA adducts and generate mutagenic OFRs. Furthermore, benzene-induced OFRs induce apoptosis. The genotoxic effects include RAS oncogene mutations and chromosomal aberrations, such as deletions/translocations. Non-genotoxic benzene effects are activation of protein kinase C, enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent proliferation, and immunologic dysregulation.1,9-12 Genetically, individuals differ greatly in the level of many enzymes, including those involved in the activation or detoxification of carcinogens. It trends in hematology