Unknown,Transcriptomics,Genomics,Proteomics

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Oncogenic CARMA1 couples NF-ÎºB and Î²-Catenin signaling in diffuse large B cell lymphomas

ABSTRACT: Constitutive activation of the anti-apoptotic NF-ÎºB signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL) that is characterized by adverse survival. Recurrent oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-ÎºB pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 mutants in the NF-ÎºB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of Î²-Catenin and its destruction complex consisting of APC, AXIN1, CK1Î± and GSK3Î² to oncogenic CARMA1. Recruitment of the Î²-Catenin destruction complex was independent of CARMA1-BCL10-MALT1 (CBM) complex formation or constitutive NF-ÎºB activation and promoted the stabilization of Î²-Catenin. Elevated Î²-Catenin expression was detected in cell lines and biopsies from ABC DLBCL that rely on chronic BCR signaling. Increased Î²-Catenin amounts alone were not sufficient to induce classical WNT target gene signatures, but could augment TCF/LEF dependent transcriptional activation in response to WNT signaling. In conjunction with NF-ÎºB, Î²-Catenin enhanced expression of immune suppressive IL-10 and repressed anti-tumoral CCL3, indicating that Î²-Catenin may induce a favorable tumor microenvironment. Thus, parallel activation of NF-ÎºB and Î²-Catenin signaling by gain-of-function mutations in CARMA1 can augment WNT stimulation and is required for maintaining high expression of distinct NF-ÎºB target genes and can thereby trigger cell intrinsic and extrinsic processes that promote DLBCL lymphomagenesis. CARMA1 mutants were expressed in BJAB, an NF-ÎºB negative GCB DLBCL lymphoma cell line. Gene expression induced by GCB DLBCL derived CARMA1 L225LI mutant was compared with the empty vector (mock) control, CARMA1 WT, CARMA1 point mutant R35A and with CARMA1 double mutant R35A/L225LI.

ORGANISM(S): Homo sapiens

SUBMITTER: Michael Grau

PROVIDER: E-GEOD-70025 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Breast cancers with HER2 overexpression are sensitive to drugs targeting the receptor or its kinase activity. HER2-targeting drugs are initially effective against HER2- positive breast cancer, but resistance inevitably occurs. We previously found that nuclear factor kappa B is hyper-activated in the subset of HER-2 positive breast cancer cells and tissue specimens. In this study, we report that constitutively active NF-ÎºB rendered HER2-positive cancer cells resistant to anti-HER2 drugs, and cells selected for Lapatinib resistance up-regulated NF-ÎºB. In both circumstances, cells were anti-apoptotic and grew rapidly as xenografts. Lapatinib-resistant cells were refractory to HER2 and NF-ÎºB inhibitors alone but were sensitive to their combination, suggesting a novel therapeutic strategy. A subset of NF-ÎºB-responsive genes was overexpressed in HER2-positive and triple-negative breast cancers, and patients with this NF-ÎºB signature had poor clinical outcome. Anti-HER2 drug resistance may be a consequence of NF-ÎºB activation, and selection for resistance results in NF-ÎºB activation, suggesting this transcription factor is central to oncogenesis and drug resistance. Clinically, the combined targeting of HER2 and NF-ÎºB suggests a potential treatment paradigm for patients who relapse after anti-HER2 therapy. Patients with these cancers may be treated by simultaneously suppressing HER2 signaling and NF-ÎºB activation. We used microarrays to detail the gene expression differences underlying the characterictic survival differences between the SKR6, SKR6-Vector, SKR6CA, and SKR6LR cell lines, which are defined as follows: SKR6: A clonal derivative of SKBR3 cells isolated by fluorescence-activated cell sorting (FACS) to enrich for elevated HER2 levels, SKR6CA: SKR6 cells retrovirally transduced with constitutively active NF-ÎºB relA/p65 (CAp65) and selected with puromycin, SKR6 vector: SKR6 cells transduced with the pQCXIP empty retroviral vector and selected with puromycin, and SKR6LR: SKR6 cells treated with increasing lapatinib concentrations (0.2 to 5 Î¼M) for several months. We sorted SKBR-3 cells by fluorescence-activated cell sorting (FACS) to enriched for cell population with elevated HER2 expression, which we termed SKR6. The following cell lines were then created from SKR6 cells: SKR6CA: SKR6 cells retrovirally transduced with constitutively active NF-ÎºB relA/p65 (CAp65), SKR6 vector: SKR6 cells transduced with the pQCXIP empty retroviral vector and selected with puromycin, and SKR6LR: SKR6 cells treated with increasing lapatinib concentrations (0.2 to 5 Î¼M) for several months.

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Oncogenic CARMA1 couples NF-ÎºB and Î²-Catenin signaling in diffuse large B cell lymphomas

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