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mRNA expression of variant Fas molecules in acute leukemia cells
1Department of Pediatrics, Mie University School of Medicine, Mie, Tsu, Japan.
Abstract:
Fas (Apo-1/CD95) is a cell membrane receptor involved in apoptotic cell death. Soluble variant forms (sFas) lacking the transmembrane domain due to alternative splicing have been identified. Up-regulation of sFas expression is reportedly implicated in prereceptorial blockage of Fas-induced apoptosis in a dose-dependent manner. We examined mRNA expression of Fas and sFas in fresh leukemia cells. All leukemia cells expressed both mRNAs of full-length Fas (FasFull) and sFas with deletion of exon6 (FasDel6). The ratio of FasFull/FasDel6 mRNA expression was not always correlated with Fas-mediated growth inhibition. Interestingly, in a 6-year-old boy with acute myelogenous leukemia, blast cells obtained at onset and at the time of bone marrow relapses expressed distinct amounts of FasDel6 mRNA. Furthermore, the level of FasDel6 expression appeared to be correlated with Fas-resistance in leukemia blasts. In addition, sFas protein levels were elevated in patients' sera at onset with subsequent return to normal levels after complete remission. These results indicated that sFas could be synthesized and released by leukemia blasts and suggested that up-regulation of Fas variant transcript might render leukemia blasts resistant to Fas-mediated growth inhibition in certain cases.
Insights
Soluble Fas (sFas) variants are released by leukemia cells, potentially blocking apoptosis. Elevated sFas levels in leukemia patients may indicate resistance to Fas-mediated cell death.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Fas (Apo-1/CD95) is a key receptor mediating apoptotic cell death.
- Soluble Fas variants (sFas), arising from alternative splicing, can inhibit Fas-induced apoptosis.
- sFas up-regulation is a potential mechanism for apoptosis resistance.
Purpose of the Study:
- To investigate the expression of Fas and sFas mRNA in leukemia cells.
- To determine the correlation between Fas variant expression and Fas-mediated apoptosis resistance in leukemia.
- To analyze sFas protein levels in patients' sera.
Main Methods:
- Analysis of FasFull and FasDel6 mRNA expression in leukemia cells.
- Correlation analysis between mRNA ratios and Fas-mediated growth inhibition.
- Measurement of sFas protein levels in patient sera at different disease stages.
Main Results:
- All leukemia cells expressed both full-length Fas (FasFull) and a soluble variant (FasDel6) mRNA.
- The FasFull/FasDel6 mRNA ratio did not consistently correlate with Fas-mediated growth inhibition.
- Distinct FasDel6 mRNA levels were observed in leukemia blasts at onset versus relapse, correlating with Fas-resistance.
- Elevated serum sFas protein levels at leukemia onset decreased upon remission.
Conclusions:
- Leukemia blasts can synthesize and release sFas.
- Increased expression of Fas variant transcripts may confer resistance to Fas-mediated apoptosis in leukemia.
- sFas could serve as a potential biomarker for disease status and apoptosis resistance in leukemia.