Abstract
Resistance to Fas-mediated apoptosis (FMA) has been implicated in the pathogenesis of hematologic malignancies. Recently, a collaborative study showed that germline Fas mutations represent a genetic risk factor for the development of Hodgkin's and non-Hodgkin lymphoma. Here, we report that transformed B cell lines from familial lymphoma patients show a range of sensitivity to Fas-mediated apoptosis with lymphocytes from two patients with a marked resistance to Fas-, but not p53-mediated cell death. Fas resistance in these cells was associated with reduced recruitment of the initiator caspase 8 compared to cFlip, an inhibitor of apoptosis, to the death-inducing signaling complex (DISC). A decreased ratio of caspase 8 to cFlip in total cell extracts as well as in the DISC was associated with a profound disturbance of the Fas signaling cascade. We propose here that the relative reduction in caspase 8 to cFlip in the Fas DISC confers a survival advantage to lymphocytes and predisposes to the development of malignancy in some familial lymphoma patients.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Aged
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Aged, 80 and over
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Apoptosis*
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Blotting, Western
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Carrier Proteins / physiology*
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Caspase 8
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Caspase 9
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Caspases / metabolism*
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Cell Line
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Death Domain Receptor Signaling Adaptor Proteins
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Drug Resistance, Neoplasm*
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Female
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Gamma Rays / adverse effects
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Humans
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Intracellular Signaling Peptides and Proteins*
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Lymphoma / genetics*
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Lymphoma / metabolism*
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Lymphoma / pathology
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Male
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Membrane Potentials / drug effects
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Middle Aged
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Mitochondria / drug effects
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Polymerase Chain Reaction
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Polymorphism, Single-Stranded Conformational
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Precipitin Tests
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Receptors, Tumor Necrosis Factor / metabolism
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Signal Transduction
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T-Lymphocytes / drug effects
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T-Lymphocytes / metabolism
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T-Lymphocytes / radiation effects
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / radiation effects
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Tumor Suppressor Protein p53 / metabolism
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fas Receptor / analysis
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fas Receptor / physiology*
Substances
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Carrier Proteins
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Death Domain Receptor Signaling Adaptor Proteins
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Intracellular Signaling Peptides and Proteins
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Receptors, Tumor Necrosis Factor
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Tumor Suppressor Protein p53
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fas Receptor
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CASP8 protein, human
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CASP9 protein, human
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Caspase 8
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Caspase 9
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Caspases