Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation
Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation
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DOI：
10.1073/pnas.1507459112
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发表时间：
2015-12-29
影响因子：
11.1
通讯作者：
Ruland, Juergen
中科院分区：
文献类型：
--
作者：
Knies, Nathalie;Alankus, Beguem;Ruland, Juergen
弥漫性大B细胞淋巴瘤的侵袭性活化B细胞样亚型的特征在于异常的B细胞受体（BCR）信号传导和组成性核因子κ-B（NF-κ B）活化，这是肿瘤细胞存活所必需的。BCR诱导的NF-κ B活化需要含半胱天冬酶募集结构域的蛋白11（CARD 11），在人弥漫性大B细胞淋巴瘤（DLBCL）中反复检测到CARD 11功能获得性突变。为了研究体内CARD11信号转导失调的后果，我们产生了条件性表达人DLBCL衍生的CARD11（L225LI）突变体的小鼠。令人惊讶的是，CARD11（L225LI）足以引发侵袭性B细胞淋巴增殖，导致出生后早期致死。CARD 11（L225 LI）与B细胞CLL/淋巴瘤10（BCL 10）和粘膜相关淋巴组织淋巴瘤易位基因1（MALT 1）组成性相关，以同时激活NF-κ B和c-Jun N-末端激酶（JNK）信号级联。BCL 10或MALT 1的遗传缺陷完全挽救了表型，并且JNK的药理学抑制与NF-κ B阻断类似，对自主增殖的CARD 11（L225 LI）表达B细胞具有毒性。此外，在原代人活化B细胞样（ABC）-DLBCL样本中观察到组成型JNK活性，并且人ABC-DLBCL细胞也对JNK抑制剂敏感。因此，我们的结果表明，CARD11/BCL 10/MALT 1信号传导的强制激活足以驱动体内转化的B细胞扩增，并将JNK途径鉴定为ABC-DLBCL的治疗靶点。
The aggressive activated B cell-like subtype of diffuse large B-cell lymphoma is characterized by aberrant B-cell receptor (BCR) signaling and constitutive nuclear factor kappa-B (NF-kappa B) activation, which is required for tumor cell survival. BCR-induced NF-kappa B activation requires caspase recruitment domain-containing protein 11 (CARD11), and CARD11 gain-of-function mutations are recurrently detected in human diffuse large B-cell lymphoma (DLBCL). To investigate the consequences of dysregulated CARD11 signaling in vivo, we generated mice that conditionally express the human DLBCL-derived CARD11 (L225LI) mutant. Surprisingly, CARD11(L225LI) was sufficient to trigger aggressive B-cell lymphoproliferation, leading to early postnatal lethality. CARD11(L225LI) constitutively associated with B-cell CLL/lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) to simultaneously activate the NF-kappa B and c-Jun N-terminal kinase (JNK) signaling cascades. Genetic deficiencies of either BCL10 or MALT1 completely rescued the phenotype, and pharmacological inhibition of JNK was, similar to NF-kappa B blockage, toxic to autonomously proliferating CARD11(L225LI)expressing B cells. Moreover, constitutive JNK activity was observed in primary human activated B cell-like (ABC)-DLBCL specimens, and human ABC-DLBCL cells were also sensitive to JNK inhibitors. Thus, our results demonstrate that enforced activation of CARD11/BCL10/MALT1 signaling is sufficient to drive transformed B-cell expansion in vivo and identify the JNK pathway as a therapeutic target for ABC-DLBCL.