Excessive apoptosis in low risk myelodysplastic syndromes (MDS)

The paradox of peripheral cytopenias despite a normo/hypercellular marrow i n MDS has been ascribed to excessive intramedullary hematopoietic cell apop tosis. Programmed cell death (PCD) in early disease might be triggered by t he BM microenvironment, mediated either through inhibitory cytokines such a s tumor necrosis factor alpha (TNF-alpha) or fas/fas ligand signaling or th rough a relative deficiency in hematopoietic growth factors. Intrinsic cell ular defects giving rise to abnormalities in cell-cell or cell-stromal inte raction, cell signaling or cell cycling may also underlie hematopoietic pro genitor apoptosis. Alternatively, an early 'hit' in the multistep pathogene sis of MDS may result in a higher proliferative rate of the neoplastic clon e. Increased apoptosis may thus represent a homeostatic process to control cell numbers. This paper shall summarize current evidence implicating a rol e for increased PCD in low risk MDS, outline possible etiologic factors and suggest potential therapeutic mechanisms whereby excessive hematopoietic p rogenitor cell apoptosis might he circumvented.