Takahashi Hidenobu, Feuerhake Friedrich, Kutok Jeffery L, Monti Stefano, Dal Cin Paola, Neuberg Donna, Aster Jon C, Shipp Margaret A
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3265-71. doi: 10.1158/1078-0432.CCR-06-0076.
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].
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)].
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).
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.
大B细胞淋巴瘤（LBCL）起源于生发中心（GC）或GC后分化阶段正常接触抗原的B细胞。正常低亲和力或自身反应性GC B细胞的阴性选择依赖于CD95（FAS）介导的凋亡。导致细胞质死亡结构域缺失的FAS突变会破坏三聚体受体的稳定性并抑制FAS介导的凋亡。当核因子κB（NFκB）靶标、细胞FADD样白介素1β转换酶抑制蛋白（cFLIP）与围绕FAS死亡结构域组装的死亡诱导信号复合物相互作用时，该凋亡途径也会受到抑制。在此，我们探讨FAS死亡结构域突变和NFκB介导的cFLIP过表达是否代表了在通过基因表达谱定义的LBCL亚型（氧化磷酸化、B细胞受体/增殖以及宿主反应性弥漫性LBCL和原发性纵隔LBCL）中解除外在凋亡途径调控的替代机制。
对一系列具有基因表达谱定义的亚型指定以及其他基因分析（t(14;18)和t(3;v)）的原发性LBCL进行FAS受体测序、鉴定FAS死亡结构域突变并评估cFLIP表达。
FAS死亡结构域缺失在氧化磷酸化肿瘤中显著更常见，这类肿瘤也更频繁地出现t(14;18)，这表明该弥漫性LBCL亚型中外在或内在途径存在结构异常。与之形成鲜明对比的是，宿主反应性肿瘤上调了多个NFκB靶基因且NFκB活性增加，其cFLIP（长型）表达水平显著更高。
这些数据表明，基因表达谱定义的LBCL亚型具有不同的机制来解除FAS介导的细胞死亡调控，更普遍地说，这些肿瘤组在其潜在的基因异常方面存在差异。
