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.

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)