Department of Cellular Signal Integration, German Research Center for Environmental Health, Institute of Toxicology, 85764 Neuherberg, Germany.
Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):272-7. doi: 10.1073/pnas.1008969108. Epub 2010 Dec 20.
The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) represents a very aggressive human lymphoma entity. Constitutive NF-κB 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-κB 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-κB activity and decreases the expression of NF-κB 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-κB in distinct ABC DLBCL cells and provide a rationale for the pharmacologic use of PI3K inhibitors in DLBCL therapy.
生发中心 B 细胞样（ABC）亚型弥漫性大 B 细胞淋巴瘤（DLBCL）是一种侵袭性很强的人类淋巴瘤。慢性活跃的 B 细胞受体（BCR）信号导致的 NF-κB 的持续激活是许多 ABC DLBCL 细胞的共同特征；然而，将 BCR 信号与 NF-κB 生存网络联系起来的途径在很大程度上是未知的。在这里，我们报告在携带 BCR 近端信号适配器 CD79B 突变的两种 ABC DLBCL 细胞系中，PI3K 和下游激酶 PDK1 的组成性活性对于细胞的存活是必需的。在这些细胞中，PI3K 的抑制降低了 NF-κB 的活性并降低了 NF-κB 靶基因的表达。此外，PI3K 和 PDK1 对于维持 MALT1 蛋白酶的活性是必需的，这促进了受影响的 ABC DLBCL 细胞的存活。这些结果表明，PI3K-PDK1 信号在不同的 ABC DLBCL 细胞中的 MALT1 蛋白酶和 NF-κB 上游具有关键功能，并为在 DLBCL 治疗中使用 PI3K 抑制剂提供了合理依据。
