Excessive apoptosis in low risk myelodysplastic syndromes (MDS)

The paradox of peripheral cytopenias despite a normo/hypercellular marrow in MDS has been ascribed to excessive intramedullary hematopoietic cell apoptosis. Programmed cell death (PCD) in early disease might be triggered by the BM microenvironment, mediated either through inhibitory cytokines such as tumor necrosis factor alpha (TNF-alpha) or fas/fas ligand signaling or through a relative deficiency in hematopoietic growth factors. Intrinsic cellular defects giving rise to abnormalities in cell-cell or cell-stromal interaction, cell signaling or cell cycling may also underlie hematopoietic progenitor apoptosis. Alternatively, an early 'hit' in the multistep pathogenesis of MDS may result in a higher proliferative rate of the neoplastic clone. Increased apoptosis may thus represent a homeostatic process to control cell numbers. This paper shall summarize current evidence implicating a role for increased PCD in low risk MDS, outline possible etiologic factors and suggest potential therapeutic mechanisms whereby excessive hematopoietic progenitor cell apoptosis might be circumvented.