Abstract
The myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, peripheral blood cytopenias, increased apoptosis and possible transformation into acute myeloblastic leukemia (AML). MDS are considered “clonal” stem cell disorders but the precise mechanism is yet unknown. Lately there has been some evidence implicating the extrinsic apoptosis pathway in the pathogenesis of these diseases. The present study included 30 cases (2001/03) classified according to WHO: 6 RA, 1 RARS, 7 RAEB type I, 3 RAEB type II, 2 RCMD, 2 MDS/MDP, and 2 aplastic anemias, 3 AML secondary to MDS and 4 control cases with normal histology. We assessed the expression of TNF-related-apoptosis-inducing ligand (TRAIL) and its receptors, of Fas, Fas-L, Fas-associated-death-domain (FADD), caspase-8, caspase-3 and DNA fragmentation factor (DFFP) by RT-PCR and by immunohistochemical staining. Results were correlated with the expression of CD34, HLA-DR15, CD15, CD20, CD68 and CD117. Patients were stratified according to the international prognostic scoring system (IPSS). Fas, Fas-L and FADD were overexpressed in low risk IPSS categories and in RA and RARS, but gradually lost their expression in more advanced stages and were not expressed in RAEB II and AML cases. This expression was inversely correlated with the expression of caspase-8 and DFFP. We observed that CD34+ and HLA-DR15+ samples were positively correlated with the expression of FADD, caspase-8 and DFFP. TRAIL was positive in normal histology and AML cases but its expression was diminished in all other samples. Our data suggest that the extrinsic apoptotic pathway may be implicated in MDS through Fas, Fas-L and FADD. RAEB II may be grouped with AML, as it shows a lesser degree of apoptosis than lower risk MDS categories. A better understanding of these diseases will allow for a better and more individualized management. This work was supported by a grant from the Terry-Fox Foundation.
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