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Prepublished online as a Blood First Edition Paper on August 15, 2002; DOI 10.1182/blood-2002-01-0096.
Submitted January 14, 2002
Accepted July 4, 2002
Fas-mediated apoptosis is important in regulating cell replication and death in trisomy 8 hematopoietic cells but not in cells with other cytogenetic abnormalities
Elaine M Sloand*, Sonnie Kim, Monika Fuhrer, Antonio M Risitano, Ryotaro Nakamura, Jaroslaw Maciejewski, John Barret, and Neal S Young
Hematology Branch, National Institutes of Health, Bethesda, MD, USA
* Corresponding author; email: sloande{at}nih.gov.
Increased apoptosis of hematopoietic progenitor cells has been implicated in the pathophysiology of cytopenias associated with myelodysplastic syndromes (MDS), and inhibition by immunosuppression may account for the success of this treatment in some patients. In this study, we examined bone marrow and peripheral blood of patients with chromosomal abnormalities associated with MDS-monosomy-7, trisomy-8, and 5q--for evidence of apoptosis. When fresh bone marrow from twenty-five patients with MDS 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 marrow. Subsequently, when unmanipulated bone marrow cells were depleted of CD3 cells, sorted based on Fas expression, and subjected to fluorescent in situ hybridization (FISH), monosomy 7 cells were over-represented in the Fas-negative population, while trisomy 8 cells were over-represented in the Fas-positive population. When staining for activated caspase 3 was performed on freshly made smears of the bone marrow and FISH performed, 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 antagonist (p<0.01), suggesting increased Fas-susceptibility of cells with trisomy 8. No change in cultures of cells with 5q- or monosomy 7 was seen. Fas antagonist facilitated the expansion of cells with trisomy 8, but there was no change in the percentage of cells expressing other karyotypic abnormalities. Cells with trisomy 8 appear to be more susceptible to Fas mediated apoptosis. This sensitivity may result from either immune recognition of the aneuploidy or on intrinsic propensity of these cells to undergo programmed cell death.
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