Apoptosis and anti-apoptotic mechanisms in the progression of MDS

Myelodysplastic syndrome (MDS), previously known as preleukemia, comprises a spectrum of heterogeneous, clonal disorders of hematopoiesis. A patient’s life expectancy may range from a few months to more than a decade. Recent studies provide some insights into the pathophysiology of MDS. One mechanism contributing to the constellation of hypercellular marrow and peripheral blood cytopenia is a significant increase in programmed cell death (apoptosis) in hematopoietic cells. Tumor necrosis factor (TNF)-α, Fas-ligand, TNF-related apoptosis inducing ligand (TRAIL) and other pro-apoptotic cytokines are upregulated in early stage/low-risk MDS, and neutralization of these signals may improve hematopoiesis. TRAIL induces apoptosis preferentially in clonal cells, which may contribute to containment of the clone. In a proportion of patients, MDS will eventually evolve to acute leukemia. This progression has been correlated with upregulation of NFκB, altered expression of adaptor molecules such as Flice inhibitory protein (FLIP), and enhanced activity of anti-apoptotic members of the Bcl-2 and the inhibitors of apoptosis protein (IAP) families. Also, the ratio of TNF receptors 1 and 2 changes in favor of receptor 2. The role of the microenvironment in the pathophysiology and progression of MDS has remained controversial, although there is evidence that stroma and matrix components, and their interactions with clonal cells, play an important role. Microarray gene expression studies are consistent with dysregulation of apoptosis, but not all data are in agreement.