Abstract | PURPOSE: 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]. EXPERIMENTAL DESIGN: 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.
|
Authors | Hidenobu Takahashi, Friedrich Feuerhake, Jeffery L Kutok, Stefano Monti, Paola Dal Cin, Donna Neuberg, Jon C Aster, Margaret A Shipp |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 12
Issue 11 Pt 1
Pg. 3265-71
(Jun 01 2006)
ISSN: 1078-0432 [Print] United States |
PMID | 16740746
(Publication Type: Journal Article)
|
Chemical References |
- CASP8 and FADD-Like Apoptosis Regulating Protein
- NF-kappa B
- Proto-Oncogene Proteins c-bcl-2
- Proto-Oncogene Proteins c-bcl-6
- fas Receptor
|
Topics |
- Apoptosis
(immunology)
- CASP8 and FADD-Like Apoptosis Regulating Protein
(genetics)
- Chromosome Aberrations
- Chromosomes, Human, Pair 14
(genetics)
- Chromosomes, Human, Pair 18
(genetics)
- DNA Mutational Analysis
(methods)
- Down-Regulation
(immunology)
- Gene Deletion
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
(genetics)
- Humans
- Lymphoma, B-Cell
(classification, genetics, immunology)
- Lymphoma, Large B-Cell, Diffuse
(classification, genetics, immunology)
- NF-kappa B
(metabolism)
- Point Mutation
- Protein Structure, Tertiary
(genetics)
- Proto-Oncogene Proteins c-bcl-2
(immunology)
- Proto-Oncogene Proteins c-bcl-6
(immunology)
- Reverse Transcriptase Polymerase Chain Reaction
(methods)
- Translocation, Genetic
(genetics)
- fas Receptor
(genetics)
|