PMID- 16740746
OWN - NLM
STAT- MEDLINE
DCOM- 20071109
LR  - 20171116
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 12
IP  - 11 Pt 1
DP  - 2006 Jun 1
TI  - 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.
PG  - 3265-71
AB  - 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.
FAU - Takahashi, Hidenobu
AU  - Takahashi H
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02115, USA.
FAU - Feuerhake, Friedrich
AU  - Feuerhake F
FAU - Kutok, Jeffery L
AU  - Kutok JL
FAU - Monti, Stefano
AU  - Monti S
FAU - Dal Cin, Paola
AU  - Dal Cin P
FAU - Neuberg, Donna
AU  - Neuberg D
FAU - Aster, Jon C
AU  - Aster JC
FAU - Shipp, Margaret A
AU  - Shipp MA
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (CASP8 and FADD-Like Apoptosis Regulating Protein)
RN  - 0 (NF-kappa B)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Proto-Oncogene Proteins c-bcl-6)
RN  - 0 (fas Receptor)
SB  - IM
MH  - Apoptosis/*immunology
MH  - CASP8 and FADD-Like Apoptosis Regulating Protein/*genetics
MH  - Chromosome Aberrations
MH  - Chromosomes, Human, Pair 14/genetics
MH  - Chromosomes, Human, Pair 18/genetics
MH  - DNA Mutational Analysis/methods
MH  - Down-Regulation/immunology
MH  - *Gene Deletion
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation, Neoplastic/*genetics
MH  - Humans
MH  - Lymphoma, B-Cell/classification/*genetics/immunology
MH  - Lymphoma, Large B-Cell, Diffuse/classification/*genetics/immunology
MH  - NF-kappa B/metabolism
MH  - Point Mutation
MH  - Protein Structure, Tertiary/genetics
MH  - Proto-Oncogene Proteins c-bcl-2/immunology
MH  - Proto-Oncogene Proteins c-bcl-6/immunology
MH  - Reverse Transcriptase Polymerase Chain Reaction/methods
MH  - Translocation, Genetic/genetics
MH  - fas Receptor/*genetics
EDAT- 2006/06/03 09:00
MHDA- 2007/11/10 09:00
CRDT- 2006/06/03 09:00
PHST- 2006/06/03 09:00 [pubmed]
PHST- 2007/11/10 09:00 [medline]
PHST- 2006/06/03 09:00 [entrez]
AID - 12/11/3265 [pii]
AID - 10.1158/1078-0432.CCR-06-0076 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3265-71. doi: 
      10.1158/1078-0432.CCR-06-0076.