Critical role of PI3K signaling for NF-κB-dependent survival in a subset of activated B-cell-like diffuse large B-cell lymphoma cells
Critical role of PI3K signaling for NF-κB-dependent survival in a subset of activated B-cell-like diffuse large B-cell lymphoma cells
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DOI：
10.1073/pnas.1008969108
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发表时间：
2011-01-04
影响因子：
11.1
通讯作者：
Krappmann, Daniel
中科院分区：
文献类型：
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作者：
Kloo, Bernhard;Nagel, Daniel;Krappmann, Daniel
弥漫性大b细胞淋巴瘤（DLBCL）的活化b细胞样（ABC）亚型代表了一种非常具有侵袭性的人类淋巴瘤实体。慢性活性B细胞受体（BCR）信号引起的组成型nf - κ B激活是许多ABC型DLBCL细胞的共同特征；然而，连接BCR信号和NF-kappa B促生存网络的途径在很大程度上是未知的。在这里，我们报告了PI3K和下游激酶PDK1的组成活性对于携带BCR近端信号接头CD79B突变的两种ABC DLBCL细胞系的生存能力至关重要。在这些细胞中，PI3K抑制降低NF-kappa B活性并降低NF-kappa B靶基因的表达。此外，PI3K和PDK1是维持MALT1蛋白酶活性所必需的，这促进了受影响的ABC DLBCL细胞的存活。这些结果表明，在不同的ABC型DLBCL细胞中，MALT1蛋白酶和NF-kappa B上游的PI3K- pdk1信号通路具有关键功能，并为PI3K抑制剂在DLBCL治疗中的药理学应用提供了理论依据。
The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) represents a very aggressive human lymphoma entity. Constitutive NF-kappa B activation caused by chronic active B-cell receptor (BCR) signaling is common feature of many ABC DLBCL cells; however, the pathways linking BCR signaling to the NF-kappa B prosurvival network are largely unknown. Here we report that constitutive activity of PI3K and the downstream kinase PDK1 are essential for the viability of two ABC DLBCL cell lines that carry mutations in the BCR proximal signaling adaptor CD79B. In these cells, PI3K inhibition reduces NF-kappa B activity and decreases the expression of NF-kappa B target genes. Furthermore, PI3K and PDK1 are required for maintaining MALT1 protease activity, which promotes survival of the affected ABC DLBCL cells. These results demonstrate a critical function of PI3K-PDK1 signaling upstream of MALT1 protease and NF-kappa B in distinct ABC DLBCL cells and provide a rationale for the pharmacologic use of PI3K inhibitors in DLBCL therapy.