Gene expression profiling suggests PCNSL to be derived from a late germinal center B cell.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE6047 | GEO | 2007/12/16
SECONDARY ACCESSION(S): PRJNA97785
REPOSITORIES: GEO
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Project description:To characterize the molecular origin of primary lymphomas of the central nervous system (PCNSL), 21 PCNSL of immunocompetent patients were investigated by microarray-based gene expression profiling. Comparison of the transcriptional profile of PCNSL with various normal and neoplastic B cell subsets demonstrated PCNSL (i) to display gene expression patterns most closely related to late germinal center B cells, (ii) to display a gene expression profile similar to systemic diffuse large B cell lymphomas (DLBCL), and (iii) to be in part assigned to the activated B cell-like (ABC) or the germinal center B cell-like (GCB) subtype of DLBCL. Experiment Overall Design: Total RNA was extracted from tissue blocks containing > 80% tumor cells using the TRIzol reagent (Invitrogen, Carlsbad, CA) and purified using RNeasy Kit (Qiagen, Valencia, CA). Double-stranded cDNA (ds-cDNA) was generated from 5 μg of total RNA using the SuperScript Double Stranded cDNA Synthesis Kit (Invitrogen) and a poly-dT oligonucleotide that contains T7 RNA polymerase initiation site (Sigma-Proligo, St. Louis, MO). The ds-cDNA was used as template to generate biotinylated cRNA by in vitro transcription using MEGA-script T7 High Yield Transcription Kit (Ambion, Austin, TX), biotin-11-CTP, and biotin-11-UTP (Perkin Elmer, Altham, MA). The biotinylated cRNA was purified by RNAeasy Kit (Qiagen) and fragmented according to the Affymetrix protocol. 15 μg of fragmented cRNA was hybridized to HG-U95Av2 microarrays (Affymetrix, Santa Clara, CA). Gene expression values were determined by GCOS1.2 software (Affymetrix) using the global scaling option.
2008-06-14 | E-GEOD-6047 | biostudies-arrayexpress
Project description:Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, with at least one-third of its patients not responding to the current chemotherapy regimen, R-CHOP. By gene expression profiling, patients with DLBCL can be categorized into two clinically relevant subtypes: activated B-cell (ABC) DLBCL and germinal center B-cell (GCB). Patients with ABC DLBCL have a worse prognosis, and are defined by chronic, overactive signaling through the B-cell receptor and NF-κB pathways. We examined the effects of the Src family kinase (SFK) inhibitor dasatinib in a panel of ABC and GCB DLBCL cell lines, and found that the ABC DLBCL cell lines are much more sensitive to dasatinib than the GCB DLBCL cell lines. However, using multiplexed inhibitor bead coupled to mass spectrometry (MIB/MS) kinome profiling competition and western blot analysis, both subtypes display inhibition of the SFKs in response to dasatinib after both short- and long-term treatment. MIB/MS analyses revealed several cell cycle kinases, including CDK4, CDK6, and the Aurora kinases, are inhibited by dasatinib treatment in the ABC DLBCL subtype, but not in the GCB DLBCL subtype. The present findings have important implications for the clinical use of dasatinib for the treatment of ABC DLBCL, either alone or in combination with other agents.
2018-12-14 | PXD009380 | Pride
Project description:Primary central nervous system lymphomas (PCNSL) are extranodal non-Hodgkin lymphomas arising within brain, spine cord or eyes and represent approximately 3% of all primary brain tumors in adults. PCNSL are histologically homogeneous- more than 90% are diffuse large B cell lymphomas - but clinically heterogeneous. Molecular basis which could explain PCNSL agressiveness are unknown due to paucity of biological material (i.e. stereotaxic biopsies). In order to identify recurrent genomic abnormalities in PCNSL, SNP arrays and CGH arrays were analyzed for 27 and 6 PCNSL cases, respectively. Fresh frozen samples were generally investigated by SNP array (Illumina 370K or 610K microarrays) and formalin-fixed paraffin-embedded tissues by CGH array (Nimblegen and Agilent microarrays) except for 3 frozen samples analyzed by CGHa.
2015-02-26 | E-MTAB-1905 | biostudies-arrayexpress
Project description:Gene expression profiling (GEP) of ARL patient samples was done to determine whether gene expression signatures derived from HIV- lymphomas retained their ability to molecularly classify HIV+ lymphomas. The GEP-based predictors robustly classified ARL tumors, distinguishing molecular Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), as well as activated B-cell-like (ABC) and germinal center B-cell-like (GCB) molecular subtypes of DLBCL. Gene expression profiles were used to identify coordinately regulated gene sets and pathways that differ between HIV+ and HIV- lymphomas of corresponding molecular subtype.
2012-07-18 | GSE17372 | GEO
Project description:Gene expression profiling (GEP) of ARL patient samples was done to determine whether gene expression signatures derived from HIV- lymphomas retained their ability to molecularly classify HIV+ lymphomas. The GEP-based predictors robustly classified ARL tumors, distinguishing molecular Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), as well as activated B-cell-like (ABC) and germinal center B-cell-like (GCB) molecular subtypes of DLBCL. Gene expression profiles were used to identify coordinately regulated gene sets and pathways that differ between HIV+ and HIV- lymphomas of corresponding molecular subtype.
2010-03-01 | GSE17189 | GEO
Project description:Primary central nervous system (CNS) lymphoma (PCNSL) is a diffuse large B cell lymphoma (DLBCL) confined to the CNS. A genome-wide gene expression comparison between PCNSL and non-CNS DLBCL was performed, the latter consisting of both nodal and extranodal DLBCL (nDLBCL and enDLBCL), to identify a “CNS signature.” Keywords: disease state analysis
2008-05-10 | GSE11392 | GEO
Project description:Germinal-center B-cell derived lymphomas (GCB-lymphomas) are the most common B-cell lymphomas in children and adults, with Burkitt Lymphomas (BL) predominating in childhood and follicular lymphoma (FL) and diffuse large B-cell lymphomas (DLBCL) predominating in older age groups. The cell-of-origin in all these lymphomas is supposed to be a germinal center B-cell and transformation of FL in DLBCL or intermediate DLBCL/BL (intL) can occur. In the framework of the German ICGC MMML-Seq we are currently exploring sequencing data of GCB-lymphomas and paired normal controls as well as normal B-cell subsets separated by FACS. This includes whole genome, transcriptome, miRNAome and whole methylome datasets.
| EGAS00001000394 | EGA
Project description:Gene expression profiling (GEP) of ARL patient samples was done to determine whether gene expression signatures derived from HIV- lymphomas retained their ability to molecularly classify HIV+ lymphomas. The GEP-based predictors robustly classified ARL tumors, distinguishing molecular Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), as well as activated B-cell-like (ABC) and germinal center B-cell-like (GCB) molecular subtypes of DLBCL. Gene expression profiles were used to identify coordinately regulated gene sets and pathways that differ between HIV+ and HIV- lymphomas of corresponding molecular subtype. Frozen tumor biopsies were obtained from 20 HIV-positive patients with an AIDS-defining lymphoma. Cases were ascertained at the University of Nebraska Medical Center and through the NCI AIDS and Cancer Specimen Resource tumor bank. Sufficient RNA for hybridization to Affymetrix U133 plus 2 arrays was obtained on 17 ARL cases. Details of all 20 HIV-positive patients can be found in the supplementary file linked below.
2010-03-07 | E-GEOD-17189 | biostudies-arrayexpress
Project description:Diffuse large B-cell lymphoma (DLBCL) represents a heterogeneous diagnostic category with distinct molecular subtypes that can be defined by gene expression profiling. However, even within these defined subtypes, heterogeneity prevails. To further elucidate the pathogenesis of these entities, we determined the expression of the tumor suppressor phosphatase and tensin homolog (PTEN) in 248 primary DLBCL patient samples. These analyses revealed that loss of PTEN was detectable in 55% of germinal center B-cell-like (GCB) DLBCLs, whereas this abnormality was found in only 14% of non-GCB DLBCL patient samples. In GCB DLBCL, the PTEN status was inversely correlated with activation of the oncogenic PI3K/ protein kinase B (AKT) pathway in both DLBCL cell lines and primary patient samples. Re-expression of PTEN induced cytotoxicity in PTEN-deficient GCB DLBCL cell line models by inhibiting PI3K/AKT signaling, indicating an addiction to this pathway in this subset of GCB DLBCLs. PI3K/AKT inhibition induced down-regulation of the transcription factor MYC. Re-expression of MYC rescued GCB DLBCL cells from PTEN-induced toxicity, identifying a regulatory mechanism of MYC expression in DLBCL. Finally, pharmacologic PI3K inhibition resulted in toxicity selectively in PTEN-deficient GCB DLBCL lines. Collectively, our results indicate that PTEN loss defines a PI3K/ AKT-dependent GCB DLBCL subtype that is addicted to PI3K and MYC signaling and suggest that pharmacologic inhibition of PI3K might represent a promising therapeutic approach in these lymphomas.
2013-07-09 | GSE45495 | GEO
Project description:Background: Germinal center B-cell (GCB) lymphomas are common in children and adults. The prognosis strongly depends on age. Subgroups of GCB-lymphomas are characterized by chromosomal translocations affecting immunoglobulin (IG) loci leading to oncogene deregulation. Methods: Novel IG translocation partners were cloned within the network “Molecular Mechanisms in Malignant Lymphomas” (MMML) by long-distance inverse polymerase chain reaction. Mature aggressive B-cell lymphomas from the MMML as well as pediatric and adult lymphoma trials were analyzed by fluorescence in situ hybridization (FISH) and immunhistochemistry. Data from 438 MMML cases characterized by gene expression profiling were mined. Results: Cloning of unknown IG partners identified a t(6;14)(p25;q32) juxtaposing the IRF4 oncogene with the IGH-locus as novel recurrent aberration in GCB lymphoma. FISH analyses of 427 mature B-cell lymphomas for IRF4 translocations revealed 20 IG/IRF4 positive lymphomas (17 IGH/IRF4, 2 IGL/IRF4, 1 IGΚ/IRF4). IG/IRF4-positive lymphomas were predominantly GCB-type diffuse large B-cell lymphomas (DLBCL) or follicular lymphoma grade 3, shared overexpression of IRF4/MUM1 and BCL6 and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas was different from other subtypes of DLBCL and a classifier for IG/IRF4 positivity containing 27 genes allowed prediction of 3 additional MMML IG/IRF4-positive cases subsequently proven by FISH. IG/IRF4-positivity was associated with a favorable outcome likely due to significant enrichment of IG/IRF4-positive lymphomas in childhood and young adulthood. Conclusions: Our results suggest IRF4 translocations to be primary genetic alterations in a novel molecularly defined subset of GC-derived lymphomas predominantly affecting children. 271 diffuse large B-Cell lymphoma samples were hybridized to HGU133A Affymetrix GeneChips.
2011-06-24 | E-GEOD-22470 | biostudies-arrayexpress