Critical role of PI3K signaling for NF-κB–dependent survival in a subset of activated B-cell–like diffuse large B-cell lymphoma cells

作者：Bernhard Kloo, Daniel Nagel, Matthias Pfeifer, Michael Grau, Michael Düwel, Michelle Vincendeau, Bernd Dörken, Peter Lenz, Georg Lenz, Daniel Krappmann · 发表于：Proceedings of the National Academy of Sciences · 年份：2010 · DOI：10.1073/pnas.1008969108 · 被引用次数：148 · 研究领域：Fungal Plant Pathogen Control、Lymphoma Diagnosis and Treatment、Toxin Mechanisms and Immunotoxins

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.