title: Critical role of PI3K signaling for NF-kappaB-dependent survival in a subset of activated B-cell-like diffuse large B-cell lymphoma cells.
abstract: 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.
authors.affiliation: Department of Cellular Signal Integration, German Research Center for Environmental Health, Institute of Toxicology, 85764 Neuherberg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kloo
authors.forename: Daniel
authors.initials: D
authors.lastname: Nagel
authors.forename: Matthias
authors.initials: M
authors.lastname: Pfeifer
authors.forename: Michael
authors.initials: M
authors.lastname: Grau
authors.forename: Michael
authors.initials: M
authors.lastname: Düwel
authors.forename: Michelle
authors.initials: M
authors.lastname: Vincendeau
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.forename: Peter
authors.initials: P
authors.lastname: Lenz
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
authors.forename: Daniel
authors.initials: D
authors.lastname: Krappmann
mesh_terms: D015153:Blotting, Western; D051925:CD79 Antigens / Q000235:genetics; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D047468:Immunoprecipitation; D016403:Lymphoma, Large B-Cell, Diffuse / Q000503:physiopathology*; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051925:CD79 Antigens; D020169:Caspases; D017931:DNA Primers; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C000631429:PDK1 protein, human; C400109:MALT1 protein, human