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Kinome profiling of Non-Hodgkin’s lymphoma reveals Tyro3 is important in primary effusion lymphoma survival

ABSTRACT: Non-Hodgkin’s lymphomas (NHL) make up the majority of lymphoma diagnoses and represent a very diverse set of malignancies. We sought to identify kinases uniquely upregulated in different NHL subtypes. Using Multiplexed Inhibitor Bead-mass spectrometry (MIB/MS), we found Tyro3 was uniquely upregulated and important for cell survival in primary effusion lymphoma (PEL). We developed an inhibitor against Tyro3 named UNC3810A, which inhibited cell growth in PEL but not in other NHL subtypes. UNC3810A also significantly inhibited tumor progression in a PEL xenograft mouse model compared to the vehicle treated animals. Our data suggests Tyro3 may be a therapeutic target for PEL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE114791 | GEO | 2019/07/10

REPOSITORIES: GEO

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Kinome profiling of Non-Hodgkin Lymphoma identifies Tyro3 as a therapeutic target in PEL

Project description:Non-Hodgkin lymphomas (NHL) make up the majority of lymphoma diagnoses and represent a very diverse set of malignancies. We sought to identify kinases uniquely upregulated in different NHL subtypes. Using Multiplexed Inhibitor Bead-mass spectrometry (MIB/MS), we found Tyro3 was uniquely upregulated and important for cell survival in primary effusion lymphoma (PEL), which is a viral lymphoma infected with Kaposi’s sarcoma-associated herpesvirus (KSHV).

2019-07-11 | PXD012087 | Pride

Kinome profiling of diffuse large B-cell lymphoma cells in response to dasatinib

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

Clinical proteomics analysis using Data Independent Acquisition-Mass Spectrometry (DIA-MS) identified classifiers for molecular characterization of Lymphoma

Project description:In this study, we conducted a proteomics analysis on 109 fresh-frozen lymph node samples from clinical patients, covering a comprehensive suite of lymphoma subtypes including B-NHL, T-NHL, HL, Lymphadenitis, Tumor metastatic lymph node (TLN), and Non-neoplastic lymph node (TNM: N0).

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Kinome profiling of Non-Hodgkin’s lymphoma reveals Tyro3 is important in primary effusion lymphoma survival

Project description:Kinome profiling of Non-Hodgkin’s lymphoma reveals Tyro3 is important in primary effusion lymphoma survival

| PRJNA472630 | ENA

Microarray-based CGH in human lymphoma cell lines.

Project description:This series represents the data set of Array CGH from the paper (submit for publication): “Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas. Mestre et all. ” and it's web supplement. The molecular nature of many secondary events in the pathogenesis of B-cell non Hodgkin lymphoma (B-NHL) remains unknown. We used high-resolution CGH to BAC microarrays to characterize the genomes of 48 B-cell non-Hodgkin lymphoma (B-NHL) cell lines of different origins. Array CGH identified, on average, 20 genomic alterations per cell line, including regional gains and losses as well as previously uncharacterized aberrations. Different genomic patterns were observed among the B-NHL subtypes. To search for possible oncogenic target genes, gene expression profiling was performed in the cell lines models. Integrative genomic and gene expression analyses have identified amplified oncogenes in B-cell non-Hodgkin lymphoma (B-NHL), but the capability of such technologies to localize tumor suppressor genes within homozygous deletions remains unexplored. Array-based comparative genomic hybridization (CGH) and gene expression microarray analysis of 48 cell lines derived from patients with different B-NHLs delineated twenty homozygous deletions at seven chromosome areas, all of which contained tumor suppressor gene targets. Further investigation revealed that only a fraction of primary biopsies presented inactivation of these genes by point mutation or intragenic deletion, but instead some of them were frequently silenced by epigenetic mechanisms. Our microarray strategy has identified novel candidate suppressors inactivated by genetic and epigenetic mechanisms that substantially vary among the B-NHL subtypes. Keywords: Array CGH, B-cell non-Hodgkin lymphoma, genomic amplification, homozygous deletion

2007-02-05 | GSE5316 | GEO

CGCI: Non-Hodgkin Lymphoma (NHL) – Follicular Lymphoma (FL)

Project description:CGCI: Non-Hodgkin Lymphoma (NHL) – Follicular Lymphoma (FL)

| PRJNA172564 | ENA

Restoring PU.1 induces apoptosis and modulates viral transactivation via interferon-stimulated genes in primary effusion lymphoma

Project description:Primary effusion lymphoma (PEL), which is an aggressive lymphoma associated with Kaposi sarcoma-associated herpesvirus/human herpes virus-8 (KSHV/HHV-8), is refractory to standard chemotherapy, and exhibits a poor prognosis. Although PU.1 is down-regulated in PEL among B-cell transcription factors, the potential role of its reduction remains to be elucidated. In this investigation, we analyzed the DNA methylation of PU.1 cis-regulatory elements in PEL and the effect of restoring PU.1 on PEL cells. The expression of PU.1 mRNA was down-regulated in PEL cells. The promoter and enhancer regions of the PU.1 gene were highly methylated. The restoration of PU.1 inhibited cell growth and induced apoptosis in PEL cells. A microarray analysis revealed that interferon-stimulated genes (ISGs) including pro-apoptotic ISGs were strongly increased in BCBL-1 cells after the induction of PU.1. The up-regulation of PU.1 induced the transactivation of pro-apoptotic ISG promoters, such as the XAF1, OAS1, and TRAIL promoters, in reporter assays. Mutations at the PU.1 binding sites suppressed its transactivation. We confirmed the binding of PU.1 to the XAF1, OAS1, and TRAIL promoters in a chromatin immunoprecipitation assay. PU.1 suppressed ORF57 activation by inducing IRF7. The reinduction of PU.1 reduced formation of ascites and lymphoma cell infiltration of distant organs in PEL xenograft model mice. These results suggest that PU.1 plays a role in tumor suppression in PEL and its down-regulation is associated with PEL development. Up-regulation of PU.1 with demethylation agents may be a novel therapeutic strategy for PEL.

2019-02-28 | GSE97318 | GEO

Clinical Impact of Circulating miR-92a Levels in Non-Hodgkin’s Lymphoma

Project description:To identify the differentially expressed miRs in the plasmas of non-Hodgkin's lymphoma (NHL) patients, we screened NHL samples using microarrays. Experiments were performed with three pooled total RNA isolated from the plasmas of four patients with diffuse large B-cell lymphoma (DLBCL), four patients with follicular lymphoma (FL), and eight control samples.

2011-12-31 | E-GEOD-22604 | biostudies-arrayexpress

Affymetrix 500K SNP array data for Primary Effusion Lymphoma samples

Project description:Affymetrix 500K array was used to determine gross genomic aberrations in a panel of Primary Effusion Lymphoma (PEL) cell lines, specifically focusing on chromosome 10, which includes the Phosphatase and Tensin Homolog (PTEN) locus. 10 PEL cell lines were hybridized to the Affymetrix 500K array where non-PEL B-cell lymphoma cell lines BJAB and DG75 were used as controls. The data was analyzed using Partek Genomic Suite software and compared to normal tonsil controls.

2011-06-23 | E-GEOD-28684 | biostudies-arrayexpress

Transcription profiling of human non-Hodgkins lymphoma (NHL) cell lines

Project description:We profiled 40 NHL cell lines to determine gene expression patterns and molecular subtypes. Experiment Overall Design: RNA profiles of NHL cell lines.

2009-05-16 | E-GEOD-15329 | biostudies-arrayexpress

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