FAS death domain deletions and cellular FADD-like interleukin 1beta converting enzyme inhibitory protein (long) overexpression: alternative mechanisms for deregulating the extrinsic apoptotic pathway in diffuse large B-cell lymphoma subtypes.
OBJECTIVE
Large B-cell lymphomas (LBCL) arise from normal antigen-exposed B cells at germinal center (GC) or post-GC stages of differentiation. Negative selection of normal low-affinity or self-reactive GC B-cells depends on CD95 (FAS)-mediated apoptosis. FAS mutations that result in deletion of the cytoplasmic death domain destabilize the trimeric receptor and inhibit FAS-mediated apoptosis. This apoptotic pathway is also inhibited when the nuclear factor kappaB (NFkappaB) target, cellular FADD-like interleukin 1beta converting enzyme inhibitory protein (cFLIP), interacts with the death-inducing signaling complex, assembled around the FAS death domain. Herein, we ask whether FAS death domain mutations and NFkappaB-mediated overexpression of cFLIP represent alternative mechanisms for deregulating the extrinsic apoptotic pathway in LBCL subtypes defined by gene expression profiling [oxidative phosphorylation, B-cell receptor/proliferation, and host response diffuse LBCLs and primary mediastinal LBCLs].


METHODS
The FAS receptor was sequenced, FAS death domain mutations identified, and cFLIP expression assessed in a series of primary LBCLs with gene expression profiling-defined subtype designations and additional genetic analyses [t(14;18) and t(3;v)].


RESULTS
FAS death domain deletions were significantly more common in oxidative phosphorylation tumors, which also have more frequent t(14;18), implicating structural abnormalities of either the extrinsic or intrinsic pathway in this diffuse LBCL subtype. In marked contrast, host response tumors, which have up-regulation of multiple NFkappaB target genes and increased NFkappaB activity, express significantly higher levels of cFLIP(long).


CONCLUSIONS
These data suggest that the gene expression profiling-defined LBCL subtypes have different mechanisms for deregulating FAS-mediated cell death and, more generally, that these tumor groups differ with respect to their underlying genetic abnormalities.
Takahashi
Hidenobu
H
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Feuerhake
Friedrich
F
Kutok
Jeffery L
JL
Monti
Stefano
S
Dal Cin
Paola
P
Neuberg
Donna
D
Aster
Jon C
JC
Shipp
Margaret A
MA
D017209:Apoptosis / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics*; D002869:Chromosome Aberrations; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D015536:Down-Regulation / Q000276:immunology; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000145:classification / Q000235:genetics* / Q000276:immunology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000145:classification / Q000235:genetics* / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D017354:Point Mutation; D017434:Protein Structure, Tertiary / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014178:Translocation, Genetic / Q000235:genetics; D019014:fas Receptor / Q000235:genetics*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D051560:Proto-Oncogene Proteins c-bcl-6; D019014:fas Receptor