Fas-mediated apoptosis is important in regulating cell replication and death in trisomy 8 hematopoietic cells but not in cells with other cytogenetic abnormalities.
Increased apoptosis of hematopoietic progenitor cells has been implicated in the pathophysiology of cytopenias associated with myelodysplastic syndromes (MDSs), and inhibition by immunosuppression may account for the success of this treatment in some patients. We examined bone marrow and peripheral blood of 25 patients with chromosomal abnormalities associated with MDS (monosomy 7, trisomy 8, and 5q-) for evidence of apoptosis. When fresh bone marrow was examined, the number of apoptotic and Fas-expressing CD34 cells was increased in patients with trisomy 8, but decreased in monosomy 7, as compared with healthy control donor marrow. Fas expression was increased in the trisomy 8 cells and decreased in the monosomy 7 cells when compared with normal cells from the same patient. Trisomy 8 cells were more likely to express activated caspase-3 than were normal cells. For bone marrow cells cultured with Fas agonist or Fas antagonist, the percentage of cells with trisomy 8 was significantly decreased in most cases after Fas receptor triggering and increased by Fas ligand (Fas-L) antagonist (P < 0.01), suggesting increased Fas susceptibility of cells with trisomy 8. No such changes were seen in cultures of cells with 5q- or monosomy 7. Fas antagonist facilitated the expansion of cells with trisomy 8 only. Cells with trisomy 8 appear to be more susceptible to Fas-mediated apoptosis. Clinical data demonstrating the responsiveness of some patients with trisomy 8 to anti-thymocyte globulin (ATG) and cyclosporine (CsA) would favor an active role of the immune system in this syndrome.
Sloand
Elaine M
EM
Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD 20892-1652, USA. sloande@nhlbi.nih.gov
Kim
Sonnie
S
Fuhrer
Monika
M
Risitano
Antonio M
AM
Nakamura
Ryotaro
R
Maciejewski
Jaroslaw P
JP
Barrett
A John
AJ
Young
Neal S
NS
D000741:Anemia, Aplastic / Q000235:genetics / Q000473:pathology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000648:ultrastructure; D002897:Chromosomes, Human, Pair 7; D002898:Chromosomes, Human, Pair 8; D003114:Colony-Forming Units Assay; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D018740:Genetic Heterogeneity; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology; D009006:Monosomy; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000473:pathology*; D014314:Trisomy; D019014:fas Receptor / Q000502:physiology*
D000911:Antibodies, Monoclonal; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases