Differential recruitment of caspase 8 to cFlip confers sensitivity or resistance to Fas-mediated apoptosis in a subset of familial lymphoma patients.
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.
Bäumler
Caroline
C
Hospital for Special Surgery, Weill Medical College of Cornell University, New York, NY 10021, USA.
Duan
Fei
F
Onel
Kenan
K
Rapaport
Beth
B
Jhanwar
Suresh
S
Offit
Kenneth
K
Elkon
Keith B
KB
D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000502:physiology*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D053418:Death Domain Receptor Signaling Adaptor Proteins; D019008:Drug Resistance, Neoplasm; D005260:Female; D005720:Gamma Rays / Q000009:adverse effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011233:Precipitin Tests; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D019014:fas Receptor / Q000032:analysis / Q000502:physiology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018124:Receptors, Tumor Necrosis Factor; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases