Apoptosis and antiapoptotic mechanisms in the progression of myelodysplastic syndrome.
Myelodysplastic syndrome (MDS), previously known as preleukemia, comprises a spectrum of heterogeneous, clonal disorders of hematopoiesis. A patient's life expectancy can range from a few months to more than a decade. Recent studies provide some insight 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)-alpha, Fas ligand, TNF-related apoptosis-inducing ligand, and other proapoptotic cytokines are upregulated in early-stage/low-risk MDS, and neutralization of these signals can improve hematopoiesis. TNF-related apoptosis inducing ligand induces apoptosis preferentially in clonal cells, which can 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 nuclear factor kappaB; altered expression of adaptor molecules, such as Flice inhibitory protein; and enhanced activity of antiapoptotic members of the Bcl-2 and inhibitors of apoptosis protein 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.
Kerbauy
Daniella B
DB
Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Seattle, WA 98109-1024, USA.
Deeg
H Joachim
HJ
D017209:Apoptosis; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction