Oncogenic CARMA1 couples NF-κB and β-catenin signaling in diffuse large B-cell lymphomas.
Oncogenic CARMA1 couples NF-κB and β-catenin signaling in diffuse large B-cell lymphomas.
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致癌性CARMA1夫妇在扩散的大B细胞淋巴瘤中NF-κB和β-catenin信号传导。
DOI：
10.1038/onc.2015.493
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发表时间：
2016-08-11
期刊：
影响因子：
8
通讯作者：
Krappmann D
中科院分区：
文献类型：
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作者：
Bognar MK;Vincendeau M;Erdmann T;Seeholzer T;Grau M;Linnemann JR;Ruland J;Scheel CH;Lenz P;Ott G;Lenz G;Hauck SM;Krappmann D
抗凋亡核因子-κB （NF-κB）信号通路的组成性激活是弥漫性大b细胞淋巴瘤（DLBCL）活化的b细胞样（ABC）亚型的标志。在连接b细胞受体（BCR）信号和典型NF-κB通路的支架蛋白CARMA1 （CARD11）中发现了复发性致癌突变。我们询问了额外的下游过程在多大程度上被激活，并有助于dlbcl衍生的CARMA1突变体的致癌潜力。为此，我们在NF-κB阴性DLBCL淋巴瘤细胞系BJAB中表达致癌基因CARMA1。通过蛋白质组学方法，我们确定了β-catenin及其由APC、AXIN1、CK1α和GSK3β组成的破坏复合体对致癌CARMA1的募集。β-catenin破坏复合物的募集不依赖于CARMA1-BCL10-MALT1复合物的形成或构成性NF-κB的激活，并促进了β-catenin的稳定。在ABC DLBCL细胞系中，β-catenin破坏复合体也被招募到CARMA1上，这与β-catenin表达升高相一致。因此，β-catenin在依赖慢性BCR信号传导的非gcb DLBCL活检中经常被检测到。单独增加β-catenin的量不足以诱导经典WNT靶基因信号，但可以增加TCF/ lef依赖的转录激活，以响应WNT信号。与NF-κB联合，β-catenin可增强免疫抑制性白细胞介素-10的表达，抑制抗肿瘤细胞CCL3，提示β-catenin可诱导良好的肿瘤微环境。因此，CARMA1中功能获得性突变平行激活NF-κB和β-catenin信号通路增强了WNT刺激，并且是调节不同NF-κB靶基因表达以触发促进DLBCL淋巴瘤发生的细胞内源性和外源性过程所必需的。
Constitutive activation of the antiapoptotic nuclear factor-κB (NF-κB) signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL). Recurrent oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-κB pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 in the NF-κB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of β-catenin and its destruction complex consisting of APC, AXIN1, CK1α and GSK3β to oncogenic CARMA1. Recruitment of the β-catenin destruction complex was independent of CARMA1-BCL10-MALT1 complex formation or constitutive NF-κB activation and promoted the stabilization of β-catenin. The β-catenin destruction complex was also recruited to CARMA1 in ABC DLBCL cell lines, which coincided with elevated β-catenin expression. In line, β-catenin was frequently detected in non-GCB DLBCL biopsies that rely on chronic BCR signaling. Increased β-catenin amounts alone were not sufficient to induce classical WNT target gene signatures, but could augment TCF/LEF-dependent transcriptional activation in response to WNT signaling. In conjunction with NF-κB, β-catenin enhanced expression of immunosuppressive interleukin-10 and suppressed antitumoral CCL3, indicating that β-catenin can induce a favorable tumor microenvironment. Thus, parallel activation of NF-κB and β-catenin signaling by gain-of-function mutations in CARMA1 augments WNT stimulation and is required for regulating the expression of distinct NF-κB target genes to trigger cell-intrinsic and extrinsic processes that promote DLBCL lymphomagenesis.