1Department of Hematology, University of Pavia School of Medicine, IRCCS Policlinico S. Matteo, Pavia; 2Dept. of Hematology, University Tor Vergata, Rome; 3Division of Hematology Oncology, Department of Pediatrics, IRCCS Policlinico S. Matteo and University of Pavia School of Medicine, Pavia; 4Section of Hematology, University of Perugia, Perugia; 5 Division of Hematology, Department of Oncology and Hematology, Niguarda Ca’Granda Hospital, Milan; 6 Department of Clinical and Biological Sciences, Ospedale San Luigi, Orbassano, Torino; 7Division of Hematology, Pesaro; 8Department of Hematology and Medical Oncology, University of Bologna and Policlinico S. Orsola, Bologna, Italy was found that the level of enzymes involved in the metabolism of benzene (eg NAD (P) H: quinone oxidoreductase) greatly influenced the risk of MDS after exposure to benzene. Likewise, glutathione S transferase levels appear to be correlated with the risk of MDS in persons exposed to industrial compounds. Greater knowledge of the relationship between enzymatic profiles and the risk of MDS could possibly lead to preventive measures in occupational medicine.

A specific multistep sequence for the development of idiopathic MDS based on cell culture, molecular and clinical research has recently been proposed. 2 In this model four pathophysiologic phases can be recognized (Table 1). In the pre-MDS phase the process is initiated by environmental, occupational or toxic exposure in genetically susceptible individuals. The early MDS phase is characterized by accelerated apoptosis of hematopoietic stem cells. In this phase an important role is played by extrinsic immunologic and microenvironmental factors. Progenitor cells damaged by toxin exposure or spontaneous mutation evoke an immunologic response. As in aplastic anemia (AA), a clonally expanded T-cell population elicits an autoimmune myelosuppression contributing to the cytopenia of MDS. 3 The evidence for an immunemediated myelosuppression in MDS has important therapeutic implications. 13 The restoration of marrow function in AA with immunosuppressive treatment has provided the rationale for using the same therapy in MDS. 14, 15 The experimental basis in support of this approach has recently been furnished by studies showing that depletion of lymphocytes increases in vitro hematopoiesis in long-term marrow cultures of patients with MDS. 16 The persisting autoimmune attack results in chronic overproduction of pro-apoptotic cytokines, produced by MDS mononuclear stem cells-tumor necrosis factor α (TNF-α) or by stromal cells-interferon γ (IFN-γ), interleukin (IL-1β) and transforming growth factor (TGF-β). Elevation of TNF-α induces, in MDS cells, increased FAS, down-regulation of Fap-1, and an increase in caspases causing apoptosis. Other extrinsic factors contributing to accelerated apoptosis are altered adhesive interactions between clonogenic hematopoietic stem cells and the underlying marrow stroma or endothelium. Excess apoptosis might be the reason for ineffective hematopoiesis and marrow failure in MDS. Another abnormality of marrow stroma is the increased angiogenesis due to the substantial production by MDS cells of vascular endothelial growth factor (VEGF). Increased density of blood