Similar Datasets
Project description:GCB subtype DLBCL with BCL2 translocation
| PRJNA744546 | ENA
Project description:Diffuse large B cell lymphomas (DLBCL) constitute a heterogeneous group of lymphomas in which germinal center B cell-like and activated B cell-like subtypes can be discerned based on pathology, clinical presentation and gene expression patterns. Testicular DLBCL form an immune-privileged site-related subgroup of DLBCL with an unfavorable prognosis. We used cDNA microarray analysis, immunohistochemistry for CD10, Bcl6 and MUM1, and somatic hypermutation analysis of the immunoglobulin heavy chain gene rearrangements to determine the subtype of primary testicular DLBCL. Immunohistochemistry revealed 14/22 testicular DLBCL with an activated B cell-like immunophenotype and 8/22 with an ambiguous immunophenotype co-expressing CD10 and high levels of MUM1. cDNA microarray analysis of these 22 and 4 additional cases showed a uniform activated B cell-like gene expression pattern in both immunophenotypes. Somatic hypermutation analysis showed a very high mutation load in 7 cases tested, but intraclonal heterogeneity was found at low level in only one of these cases. We conclude that primary testicular DLBCL have uniform activated B cell-like subtype characteristics despite a number of cases showing an ambiguous immunophenotype. Keywords: Gene expression
2006-05-01 | GSE4296 | GEO
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:SOX9 was identified as a prognostic biomarker particularly in IGH-BCL2 translocated germinal center B cell (GCB) subtypes of the diffuse large B cell lymphoma (DLBCL) and plays a vital role in lymphomagenesis. However, the molecular mechanism that modulating the aberrant expression of SOX9 in this DLBCL subset remains unknown. We have demonstrated that SOX9 enhanced IGH-BCL2 positive DLBCL subset resistance to either chemotherapy or BCL2 inhibitor. Moreover, we found that inhibition of BCL2 downregulates SOX9 in IGH-BCL2 positive DLBCL subset. We further identified that IRF4 is a key regulator to mediate BCL2 induced SOX9 expression, alongside with the chip-seq confirmed that IRF4 is a key transcription factor for SOX9 in DLBCL. In addition, BCL2 promote IRF4 entry into the nucleus by enhancing its protein stability, via downregulating of proteosome ubiquitination process, and, therefore, enforce SOX9-mediated phenotypes. Finally, we showed in DLBCL cell lines and xenografted mice model that in vivo inhibition of IRF4 with hIRF4 antisense oligonucleotide (ASO) repressed lymphomagenesis and DLBCL chemoresistance. Altogether, our data support the conclusion that IRF4 plays an essential role in BCL2 induced upregulation of SOX9 expression, and targeting IRF4 may represent a promising therapeutic strategy to cure relapse and refractory DLBCL in the future.
2024-09-30 | GSE278092 | GEO
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: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: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:Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most prevalent B-lymphocyte neoplasms in which abnormal activation of the Bruton’s tyrosine kinase (BTK)–mediated B-cell receptor (BCR) signaling pathway contributes to pathogenesis. Ibrutinib is an oral covalent BTK inhibitor that has shown some efficacy in both indications. To improve ibrutinib efficacy through combination therapy, we first investigated differential gene expression in parental and ibrutinib-resistant cell lines to better understand the mechanisms of resistance. Ibrutinib-resistant TMD8 cells had higher BCL2 gene expression and increased sensitivity to ABT-199, a BCL-2 inhibitor. Consistently, clinical samples from ABC-DLBCL patients who experienced poorer response to ibrutinib had higher BCL2 gene expression. We further demonstrated synergistic growth suppression by ibrutinib and ABT-199 in multiple ABC-DLBCL, GCB-DLBCL, and FL lymphoma cell lines. The combination of both drugs also reduced colony formation, increased apoptosis, and inhibited tumor growth in a TMD8 xenograft model. A synergistic combination effect was also found in ibrutinib-resistant cells generated by either genetic mutation or drug treatment. Together, these findings suggest a potential clinical benefit from ibrutinib and ABT-199 combination therapy.
2017-04-30 | GSE93984 | GEO
Project description:We studied 498 de-novo adult DLBCL cases, which had been diagnosed between January 2002 and October 2009, as part of the International DLBCL Rituximab-CHOP Consortium Program Study We perform global gene expression profiling from formalin fixed paraffin embedded 498 DLBCL tissues RNA by SPIA mediated microarray detection and identified the distinct subgroups of the disease within DLBCL, known as germinal-center-B-cell-like (GCB), activated B-cell-like (ABC), and unclassified DLBCL (UC).
2012-08-01 | GSE31312 | GEO