Selective dysregulation of ROCK2 activity promotes aberrant transcriptional networks in ABC diffuse large B cell lymphoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE147521 | GEO | 2021/06/17
REPOSITORIES: GEO
Similar Datasets
Project description:Selective dysregulation of ROCK2 activity promotes aberrant transcriptional networks in ABC diffuse large B cell lymphoma
| PRJNA615146 | ENA
Project description:Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive subtype of lymphoma usually associated with inferior outcomes. ABC-DLBCL exhibits plasmablastic features and is characterized by aberrancies in the molecular networks controlled by IRF4. The signaling pathways that are dysregulated in ABC-DLBCL are, however, not fully understood. ROCK2 is a serine-threonine kinase whose role in lymphomagenesis is unknown. Here we show that ROCK2 activity is constitutively dysregulated in ABC-DLBCL but not in GCB-DLBCL and BL. We furthermore show that ROCK2 phosphorylates IRF4 and that the ROCK2-mediated phosphorylation of IRF4 modulates its ability to regulate a subset of target genes. In addition to its effects on IRF4, ROCK2 also controls the expression of MYC in ABC-DLBCL by regulating MYC protein levels. ROCK inhibition furthermore selectively decreases the proliferation and survival of ABC-DLBCL in vitro and inhibits ABC-DLBCL growth in xenograft models. Thus, dysregulated ROCK2 activity contributes to the aberrant molecular program of ABC-DLBCL via its dual ability to modulate both IRF4- and MYC-controlled gene networks and ROCK inhibition could represent an attractive therapeutic target for the treatment of ABC-DLBCL.
| S-EPMC7403583 | biostudies-literature
Project description:Knowledge of essential oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells bearing an oncogenic mutation while sparing normal cells. Lenalidomide is emerging as an active agent in diffuse large B cell lymphoma (DLBCL), especially for the activated B cell-like (ABC) subtype, but the mechanism of its action is unknown. Here we show that lenalidomide kills ABC DLBCL cells by augmenting the production of interferon 3/4, which these cells are predisposed to produce by their oncogenic MYD88 mutations. Lenalidomide stimulates the type I interferon pathway by suppressing IRF4, a repressor of IRF7. IRF4 is required for ABC DLBCL viability and is both a target and an amplifier of NF-kB signaling in this lymphoma subtype. Blockade of B cell receptor (BCR) signaling synergized with lenalidomide to reduce IRF4 levels, increase interferon 3/4 secretion, decrease NF-kB, and kill ABC DLBCL cells, suggesting therapeutic combinations that exploit the oncogenic signaling pathways in this cancer.
2012-08-16 | GSE33012 | GEO
Project description:Knowledge of essential oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells bearing an oncogenic mutation while sparing normal cells. Lenalidomide is emerging as an active agent in diffuse large B cell lymphoma (DLBCL), especially for the activated B cell-like (ABC) subtype, but the mechanism of its action is unknown. Here we show that lenalidomide kills ABC DLBCL cells by augmenting the production of interferon 3/4, which these cells are predisposed to produce by their oncogenic MYD88 mutations. Lenalidomide stimulates the type I interferon pathway by suppressing IRF4, a repressor of IRF7. IRF4 is required for ABC DLBCL viability and is both a target and an amplifier of NF-kB signaling in this lymphoma subtype. Blockade of B cell receptor (BCR) signaling synergized with lenalidomide to reduce IRF4 levels, increase interferon 3/4 secretion, decrease NF-kB, and kill ABC DLBCL cells, suggesting therapeutic combinations that exploit the oncogenic signaling pathways in this cancer. For the OCILY10 cell line treated with 10 uM lenalidamide, a four point time course of 3, 6, 24, and 48 hours was analyzed (n=4). For the TMD8 cell line treated with 10 uM lenalidamide, a four point time course of 3, 6, 24, and 48 hours was analyzed (n=4).
2012-08-16 | E-GEOD-33012 | biostudies-arrayexpress
Project description:High expression of the FOXP1 transcription factor distinguishes the highly aggressive Activated B Cell (ABC) type of Diffuse Large B Cell Lymphoma (DLBCL) from the more indolent Germinal Center (GCB) DLBCL subtype and is correlated with poor prognosis. A genetic or functional role for FOXP1 in lymphomagenesis and/or tumor maintenance, however, remains unknown. Here, we report that sustained expression of FOXP1 is necessary for ABC DLBCL cell line survival. Genome-wide transcript profiling reveals that FOXP1 acts directly and indirectly by enforcing expression of known ABC DLBCL hallmarks, including the classical NF-kappaB survival pathway. Our data further suggest that FOXP1 maintains the ABC subtype distinction by repressing gene expression programs dominant in GCB DLBCL and supports a model in which the target of ABC DLBCL transformation is a transitory cell type en route from the germinal center B cell to the terminally differentiated plasma cell.
2015-12-01 | GSE64586 | GEO
Project description:miRNA profiling of human Diffuse Large B Cell Lymphoma (DLBCL) cell lines derived from the two main subtypes of this disease: Activated B Cell like (ABC-DLBCL) and Germinal Center B cell like (GCB-DLBCL), analyzing the 711 human miRNAs present in miRBase V10.0. Five ABC-like DLBCL cell lines (RIVA, Oci-Ly3, Oci-Ly10, HBL1 and U2932) and three GCB-like DLBCL cell lines (Oci-Ly7, Oci-Ly19 and SUDHL-6) were cultured in IMDM (Cellgro) with 20% human plasma, 1% penicillin/streptomycin/L-glutamine (Cellgro,) and 0,2% beta mercaptoethanol (Invitrogen). Total RNA was extracted from cell pellets using the mirVana™ miRNA Isolation Kit (Ambion), and sent to LC Sciences facility for microarray hybridization using microfluidics technology. FirstChoice® Human Skeletal Muscle Total RNA (Ambion) was used as common reference for all hybridizations. Background substracted and normalized data from each channel was used to calculate log ratios sample/reference. Keywords: miRNA profiling
2009-01-28 | GSE12933 | GEO
Project description:RNA interference screens identified the transcription factor IRF4 as essential for the survival of the activated B-cell-like subtype of diffuse large B-cell lymphoma (ABC-DLBCL). Analysis of IRF4 genomic targets in ABC-DLBCL and Multiple Myeloma (MM) revealed that IRF4 regulates distinct networks in these cancers. IRF4 peaks in ABC-DLBCL, but not MM, were enriched for a composite ETS-IRF DNA motif that can be bound by heterodimers of IRF4 and the ETS-family transcription factor SPIB, whose expression is also essential for ABC-DLBCL survival. Gene expression and ChIP-Seq analysis identified essential genes co-regulated by IRF4 and SPIB. Together, these factors regulate a critical oncogenic loop by activating CARD11, which controls ABC-DLBCL survival via the NF-kB pathway. The interaction between IRF4 and SPIB presents an attractive therapeutic target in this aggressive lymphoma.
2012-08-16 | GSE32456 | GEO
Project description:Despite the effectiveness of immuno-chemotherapy, 40% of patients with diffuse large B-cell lymphoma (DLBCL) experience relapse or refractory disease. Longitudinal studies have previously focused on the mutational landscape of relapse but falling short of providing a consistent relapse-specific genetic signature. In our study, we have focussed attention on the changes in gene expression profile accompanying DLBCL relapse using archival paired diagnostic/relapse specimens from 38 de novo DLBCL patients. Cell of origin remained stable from diagnosis to relapse in 80% of patients, with only a single patient showing COO switching from ABC to GCB. Analysis of the transcriptomic changes that occur following relapse suggest ABC and GCB relapses are mediated via different mechanisms. We developed a 30-gene discriminator for ABC-DLBCLs derived from relapse-associated genes, that defined clinically distinct high and low risk subgroups in ABC-DLBCLs at diagnosis in datasets comprising both population-based and clinical trial cohorts. This signature also identified a population of <60-year-old patients with superior PFS and OS treated with Ibrutinib-R-CHOP as part of the PHOENIX trial. Altogether this new signature adds to the existing toolkit of putative genetic predictors now available in DLBCL that can be readily assessed as part of prospective clinical trials.
2023-03-08 | GSE193566 | GEO
Project description:Comparing the effects of artesunate versus DMSO in three DLBCL cell lines, we found a decrease in cell viability to 80%-60%. Over increasing artesunate dosage,we found increasing ROS generation and lipid peroxidation. In combination with the Ferrostatin-1 rescue experiment, we conclude that cell death induced by artesunate is ferroptotic. We compared the transcriptome of the U2932 cell line with and without 100µm artesunate in triplicate. A ferroptosis gene signature is shown to be enriched among the upregulated genes of this comparison. GPX4 protein expression was shown to be downregulated after artesunate in U2932 cells, but not in the rescue experiment with Ferrostatin-1. MT1G gene expression was identified as required for artesunate-mediated ferroptosis via targeted suppression by shRNAs. We present significantly decreased cell viability when combining artesunate with doxorubicin, suggesting a potential translation into clinic for treatment of ABC and GCB DLBCL.
2024-03-06 | GSE260741 | GEO
Project description:miRNA profiling of human Diffuse Large B Cell Lymphoma (DLBCL) cell lines derived from the two main subtypes of this disease: Activated B Cell like (ABC-DLBCL) and Germinal Center B cell like (GCB-DLBCL), analyzing the 711 human miRNAs present in miRBase V10.0. Five ABC-like DLBCL cell lines (RIVA, Oci-Ly3, Oci-Ly10, HBL1 and U2932) and three GCB-like DLBCL cell lines (Oci-Ly7, Oci-Ly19 and SUDHL-6) were cultured in IMDM (Cellgro) with 20% human plasma, 1% penicillin/streptomycin/L-glutamine (Cellgro,) and 0,2% beta mercaptoethanol (Invitrogen). Total RNA was extracted from cell pellets using the mirVana™ miRNA Isolation Kit (Ambion), and sent to LC Sciences facility for microarray hybridization using microfluidics technology. FirstChoice® Human Skeletal Muscle Total RNA (Ambion) was used as common reference for all hybridizations. Background substracted and normalized data from each channel was used to calculate log ratios sample/reference. Keywords: miRNA profiling Dual channel experiments using FirstChoice® Human Skeletal Muscle Total RNA (Ambion) as common reference for all hybridizations. Reference was labeled with Cy5 and the cell line extracted RNA with Cy3. Biological replicates: 5 ABC-DLBCL cell lines and 3 GCB-DLBCL cell lines. Microarray hybridization was performed at LC Sciences, using slides containing in situ synthesized oligonucleotides to detect the 711 miRNAs present in miRBase V10.0. Probes hsa-miR-337 and hsa-miR-542-5p were excluded due to systematic dye bias, according to the manufacturer intructions. Background substracted and normalized detectable data was used to calculate log ratios sample/reference. Background is determined using a regression-based background mapping method. The regression is performed on 5% to 25% of the lowest intensity data points excluding blank spots. Raw data matrix is then subtracted by the background matrix. Normalization was carried out using a LOWESS (Locally-weighted Regression) method on the background-subtracted data. A transcript to be listed as detectable must meets at least two conditions: signal intensity higher than 3×(background standard deviation) and spot CV < 0.5. CV is calculated by (standard deviation)/(signal intensity). When repeating probes are present on an array, a transcript is listed as detectable only if the signals from at least 50% of the repeating probes are above detection level.
2009-01-27 | E-GEOD-12933 | biostudies-arrayexpress