Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1152334 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30418300.fastq.gz | Fastqsanger.gz | |||
| SRR30418302.fastq.gz | Fastqsanger.gz | |||
| SRR30418305.fastq.gz | Fastqsanger.gz | |||
| SRR30418307.fastq.gz | Fastqsanger.gz | |||
| SRR30418308.fastq.gz | Fastqsanger.gz |
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Project description:Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is a rare extranodal lymphoma subtype. This retrospective study elucidates the currently unknown genetic background of a large clinically well-annotated cohort of DLBCL with osseous localizations (O-DLBCL), including PB-DLBCL. 103 O-DLBCL patients were included and compared with 63 (extra)nodal non-osseous (NO)-DLBCLs with germinal center B-cell phenotype (NO-DLBCL-GCB). Cell-of-origin (COO) was determined by immunohistochemistry and gene-expression-profiling (GEP) using (extended)-NanoString/Lymph2Cx. Mutational profiles were identified with targeted next-generation deep-sequencing, including 52 B-cell lymphoma-relevant genes. O-DLBCLs, including 34 PB-DLBCL, were predominantly classified as GCB-phenotype based on immunohistochemistry (74%) and NanoString analysis (88%). Unsupervised hierarchical clustering of an extended-NanoString/Lymph2Cx demonstrated significantly different GEP-clusters for PB-DLBCL as opposed to NO-DLBCL-GCB (P<0.001). Expression levels of 23 genes of two different targeted GEP-panels, indicated a centrocyte–like phenotype for PB-DLBCL, whereas NO-DLBCL-GCB showed a centroblast-like constitution. PB-DLBCL had significantly more frequent mutations in four GCB-associated genes, i.e. B2M, EZH2, IRF8, and TNFRSF14, compared to NO-DLBCL-GCB (P=0.031, P=0.010, P=0.047, and P=0.003). PB-DLBCL with its corresponding specific mutational profile were significantly associated with a superior overall survival compared to equivalent Ann Arbor limited-stage I/II NO-DLBCL-GCB (P=0.011). This study is the first to demonstrate that PB-DLBCL is characterized by a GCB-phenotype, with a centrocyte-like GEP-pattern and a GCB-associated mutational profile (both involved in immune surveillance) and a favorable prognosis. These novel biology-associated features provide evidence that PB-DLBCL represents a distinct extranodal DLBCL entity and its specific mutational landscape holds potential for targeted therapies (e.g. EZH2-inhibitors). The NanoString analsyis consisted out of 219 probes for Lymph2Cx classifier (COO), MYC-activity GEP score, CNV-associated GEP signature, consensus clustering, and immune-ratio signature. This custome probeset was used to differentiate GEPs between osseous and non-osseos DLBCL of the GCB-phenotype.
2021-06-04 | GSE176126 | GEO
Project description:This study performed an in-depth investigation of the immune-molecular profiles of an unique cohort of extranodal diffuse large B-cell lymphoma (DLBCL) of the bone, with single primary bone (PB-)DLBCL and multiple localizations (polyostotic-DLBCL). A similar DLBCL cohort with nodal localizations only and germinal center B-cell (GCB) phenotype (nodal-DLBCL-GCB) was used as comparator. With comprehensive genomic mutational and gene gene-expression profiling (GEP), in total 103 DLBCLS were analyzed. Both molecular techniques revealed a shared mutational genomic and gene-expression transcriptomic profile for PB-DLBCL (n=51) and polyostotic-DLBCL (n=18), justifying a collective analysis as bone-DLBCL. Differential incidences of EZH2, IRF8, and HIST1H1E, and MYC mutations/rearrangements (p<0.05) confirmed the distinct oncogenic evolution of bone-DLBCL and nodal-DLBCL-GCB (n=34). Bone-DLBCL primarily exhibited an intermediate/rich immune TME GEP signature (p≤<0.005), based on published gene sets. Further unsupervised clustering identified two distinct groups, establishing a notable ‘immune-rich’ cluster dominated by bone-DLBCL (754%, p=0.0062). This immune-rich cluster demonstrated superior survival (p=≤0.0263) compared to the ‘immune-low’ cluster, which consisted mostly of nodal-DLBCL-GCB cases (61%). Gene-set enrichment analysis illustrated variations in cell proliferation and immune systemreceptor pathways for the immune-rich cluster (p<0.001), indicating a crucial role for the tumor microenvironment (TME) in disease behavior and outcome. Further supported by deconvolution applications (CIBERSORTx and single-sample gene-set enrichment analysis), The immune-rich cluster highlighted highlighting an abundantmainly regulatory T cells in immune-rich and cell proliferation in immune-low. infiltrate of NK/T, Treg, TFH and follicular dendritic cells (p<0.001). Conclusively, PB-DLBCL and polyostotic-DLBCL shared similar TME features and immune-molecular profiles. This study delineates tThe distinct immune-rich TME profile of bone-DLBCL, which is associated with a superior survival. These findings suggest that bone-DLBCL patients with immune-rich GEP might benefit from less intensive polychemotherapies and this could further shape targeted immunomodulatory strategies.
2025-04-22 | GSE273595 | GEO
Project description:Gene-expression profiling of a polyostotic-DLBCL and primary bone-DLBCL cohort compared to a nodal DLBCL GCB.
| PRJNA1142483 | ENA
Project description:Background: High-grade B-cell lymphoma with 11q aberration (HGBCL-11q) is a rare germinal centre lymphoma with a typical gain/loss pattern on chromosome 11q, but without MYC translocation and with some features resembling Burkitt lymphoma (BL) and HGBCLs or germinal centre derived diffuse large B-cell lymphoma, not otherwise specified (GCB-DLBCL-NOS). The microRNA expression profile of HGBCL-11q is not characterised. We aim to analyse miRNA expression profile in HGBCL-11q, BL and in GCB-DLBCL-NOS. Methods: Next generation sequencing (NGS)-based microRNA profiling was performed for HGBCL-11q (n=6), BL (n=8), and also GCB-DLBCL-NOS without (n=3) and with MYC rearrangement (MYC-R) (n=7). Results: We identified 39 and 64 miRNAs differentiating HGBCL-11q from BL, and from GCB-DLBCL-NOS without MYC-R, respectively. We found that the expression level of miR-223-3p, miR-193b-3p, miR-29b-3p and miR-146a-5p simultaneously differentiated HGBCL-11q from BL, as well as from GCB-DLBCL-NOS without MYC-R. We found higher miRNA profile heterogeneity in HGBCL-11q than in BL. The analysis of MYC-regulated miRNA showed different profile in HGBCL-11q and in BL but demonstrated separation of HGBCL-11q and BL from GCB-DLBCL-NOS cases. Conclusion: microRNA profile of HGBCL-11q is different than that of BL and of GCB-DLBCL-NOS but more heterogeneous compared to BL.
2025-01-15 | GSE281999 | GEO
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:Diffuse large B-cell lymphoma (DLBCL) represents a heterogeneous diagnostic category with distinct molecular subtypes that can be deM-oM-,M-^Aned by gene expression proM-oM-,M-^Aling. However, even within these deM-oM-,M-^Aned 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. Reexpression of PTEN induced cytotox- icity in PTEN-deM-oM-,M-^Acient 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. Reexpression 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-deM-oM-,M-^Acient GCB DLBCL lines. Collectively, our results indicate that PTEN loss deM-oM-,M-^Anes 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. This GEO dataset is comprised of a) GEP measurements for 34 primary DLBCL patient samples plus two reference samples, b) 8 paired GEP measurements of the HT DLBCL cell line and c) aCGH measurements for two DLBCL cell lines in addition to previously published cell lines in GSE43272 (i.e., Sample GSM1059798). All of these data were used in the paper cited below.
2013-07-09 | E-GEOD-45495 | biostudies-arrayexpress
Project description:Germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is one of the most common subtypes of B-cell non-Hodgkin lymphoma. The tumor microenvironment (TME) is responsible for therapy resistance and relapse in GCB-DLBCL, while most studies have focused on targeting tumor cells instead of the TME. Stromal cells are the main component of the TME in GCB-DLBCL. How stromal cells interact with GCB-DLBCL tumor cells and protect GCB-DLBCL from cell death remain elusive. Here we reported that a CD40/RANK pathway-mediated positive feedback loop mediated the interaction of stromal cells and GCB-DLBCL to enhance the survival of GCB-DLBCL tumor cells. The viability of primary GCB-DLBCL patient-derived xenograft tumor cells was increased when they were cocultured with different tissue-derived stromal cells. We demonstrated that stromal cells promoted tumor cell survival not only through excreted cytokines but also depending more on direct contact. Furthermore, CD40 ligand (CD40L) expressed on stromal cells activated CD40 signaling in tumor cells, protecting tumor cells from apoptosis and upregulating RANK ligand (RANKL). RANK activation by RANKL in tumor cells enhanced the expression of CD40L and BAFF in stromal cells, both of which in turn promoted tumor cell survival through activating canonical and noncanonical NF-B signaling. In addition, CD40 activation upregulated the expression of KDM6B, and KDM6B further mediated the activation of canonical and noncanonical NF-B signaling, the downstream signaling pathways of the CD40 activation, all leading to tumor cell survival. These results further suggest that CD40-KDM6B-NF-B axis serve as a potential target for GCB-DLBCL therapy.
2022-05-09 | GSE202370 | GEO
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:The goal of this study is to identify the effect of the transcription factor STAT3 in the two major subtypes of diffuse large B cell lymphoma (DLBCL). STAT3 is a signal transducer that, when dysregulated, becomes a powerful oncogene found in many human cancers, including DLBCL. DLBCL is the most common form of non-Hodgkin’s lymphoma and has two major subtypes: germinal center B-cell-like (GCB) and activated B-cell-like (ABC). When compared to the GCB form, ABC lymphomas respond much more poorly to current therapies and often exhibit overexpression or overactivation of STAT3. To investigate how STAT3 might contribute to this aggressive phenotype, we have used ChIP-Seq to identify STAT3 binding sites in 8 DLBCL cell lines (4 GCB subtype, 4 ABC) that are derived from patient tumors. 10,337 distinct STAT3 binding regions are occupied in at least two of the eight cell lines. One third (n = 3524) are differentially bound by STAT3 between the two subtypes (FDR < 0.05). More BRs are strongly bound in ABC than in GCB: 44% of differentially bound BRs (n = 1550) show more STAT3 binding in GCB, while 56% (n = 1974) are more strongly bound in ABC. Identification and comparison of STAT3 transcription factor binding sites in 8 cell lines that represent the 2 subtypes of DLBCL. 4 cell lines are subtyped as ABC and 4 are subtyped as GCB. 2-9 replicates and 1 input control are present for each cell line. (Cell line OCI-Ly19 was not included in the final analysis because RNA-Seq showed that its gene expression clustered in between the subtypes, probably due to its EBV+ status. However, its peak calls were used in intermediate steps of the analysis pipeline. Its sequencing runs have been included for completeness.)
2013-12-16 | E-GEOD-50723 | biostudies-arrayexpress
Project description:Genome studies of diffuse large B-cell lymphoma (DLBCL) have revealed a large number of somatic mutations and structural alterations that may contribute to their heterogeneous behavior. However, their clinical relevance and potential interest in identifying appropriate candidate drugs for personalized management are not well known. In this study, targeted next generation sequencing and genomic copy number alterations (CNA) were analyzed in 150 cases of diffuse large B-cell lymphoma (DLBCL) to define the clinical significance of recurrent genomic alterations and to identify potential targets for personalized management. An independent cohort of 111 patients was also analyzed to confirm the clinically significant findings. We found a differential profile of mutations, altered pathogenic pathways and CNA in germinal center B (GCB) and activated B-cell (ABC)-DLBCL with some shared alterations in both subtypes. Mutations in genes of the NOTCH pathway and tumor suppressor genes (TP53/CDKN2A), but not individual genes, conferred an unfavorable prognosis that was independent of other parameters and confirmed in the validation cohort. Tumors with NOTCH pathway mutations had a significant overexpression of downstream target genes, emphasizing the relevance of this pathway in DLBCL. We identified other new relevant genes including TMEM30A, RHOA, EBF, and TOX, among others. In silico drug discovery analysis recognized 69 (46%) cases carrying at least one genomic alteration considered a potential target of drug response according to early clinical trials (n=66) or pre-clinical assays (n=3) in DLBCL or other lymphomas. These findings orient future preclinical and clinical intervention strategies in DLBCL.
2018-03-14 | GSE94705 | GEO