Low frequency of FAS mutations in Reed-Sternberg cells of Hodgkin's lymphoma.
Reed-Sternberg (RS) cells, the neoplastic elements of Hodgkin's lymphoma (HL), usually lack B-cell receptor expression. Normal germinal center B cells, with lack of or low-affinity B-cell receptor expression, are eliminated via FAS-induced apoptosis. RS cells express FAS, but are rescued from apoptosis by a transforming event. It is known that HL-derived cell lines are resistant to FAS-mediated apoptosis. To investigate potential causes for this resistance, FAS mutations and c-FLIP expression were studied in four HL-derived cell lines and 20 cases of HL. L1236 was found to have a splice donor site mutation in intron 7 that resulted in an aberrantly spliced FAS transcript. Screening of microdissected RS cells revealed loss of heterozygosity for a known exon 7 polymorphism in two of six informative cases indicating loss of one FAS allele. In one of the two cases with loss of heterozygosity a hemizygous mutation was detected in exon 9. c-FLIP expression was observed in all HL cell lines and in RS cells of all HL cases. Our data show that FAS mutations are rare and suggest that overexpression of c-FLIP, which was present in all cases, is involved in the resistance to FAS-mediated apoptosis.
Maggio
Ewerton M
EM
Department of Pathology and Laboratory Medicine, University Medical Center Groningen, The Netherlands.
Van Den Berg
Anke
A
de Jong
Debora
D
Diepstra
Arjan
A
Poppema
Sibrand
S
D017209:Apoptosis / Q000235:genetics; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000096:biosynthesis; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D015321:Gene Rearrangement; D005803:Genes, Immunoglobulin; D006689:Hodgkin Disease / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009154:Mutation; D016539:Reed-Sternberg Cells / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019014:fas Receptor