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

Item Type:Article
Title:Critical role of PI3K signaling for NF-κB-dependent survival in a subset of activated B-cell-like diffuse large B-cell lymphoma cells
Creators Name:Kloo, B. and Nagel, D. and Pfeifer, M. and Grau, M. and Duewel, M. and Vincendeau, M. and Doerken, B. and Lenz, P. and Lenz, G. and Krappmann, D.
Abstract:The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) represents a very aggressive human lymphoma entity. Constitutive NF-kappaB 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-kappaB 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-kappaB activity and decreases the expression of NF-kappaB 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-kappaB in distinct ABC DLBCL cells and provide a rationale for the pharmacologic use of PI3K inhibitors in DLBCL therapy.
Keywords:Caspases, CD79 Antigens, Cell Survival, Chromatin Immunoprecipitation, DNA Primers, Electrophoretic Mobility Shift Assay, Flow Cytometry, Gene Expression Profiling, Immunoprecipitation, Large B-Cell Diffuse Lymphoma, NF-kappa B, Neoplasm Proteins, Phosphatidylinositol 3-Kinases, Protein-Serine-Threonine Kinases, Signal Transduction, Tumor Cell Line, Western Blotting
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:108
Number:1
Page Range:272-277
Date:4 January 2011
Official Publication:https://doi.org/10.1073/pnas.1008969108
PubMed:View item in PubMed

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