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FAS Death Domain Deletions and Cellular FADD-like Interleukin 1ß Converting Enzyme Inhibitory Protein (Long) Overexpression: Alternative Mechanisms for Deregulating the Extrinsic Apoptotic Pathway in Diffuse Large B-Cell Lymphoma Subtypes

Authors' Affiliations: Departments of ¹ Medical Oncology and ² Biostatistics, Dana-Farber Cancer Institute; ³ Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and ⁴ Broad Institute, Cambridge, Massachusetts

Requests for reprints: Margaret A. Shipp, Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: 617-632-3874; Fax: 617-632-4734; E-mail: margaret_shipp{at}dfci.harvard.edu.

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 B (NFB) target, cellular FADD-like interleukin 1ß 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 NFB-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 NFB target genes and increased NFB 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.