Increased CCL2/CCR2 axis in MYC/BCL2 double-expressor DLBCL promotes tumor progression by increasing M2 macrophages
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1062058 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The pathogenesis of c-MYC and BCL2 double-expressor diffuse large B cell lymphoma (DE DLBCL) remains unclear, particularly in terms of the tumor microenvironment. We aimed to analyze the immune microenvironment of DE DLBCLs to understand the basis of DE-DLBCL's aggressiveness and identify potential therapeutic targets. To discover the key features of DE-DLBCL, fourteen non-DE and 14 DE DLBCL samples underwent RNA-seq analysis. For validation, formalin-fixed paraffin-embedded tissues from 126 patients were immunostained for CD3, CD4, CD8, FOXP3, CD68 and CD163. Two c-MYClow/BCL2low DLBCL (SU-DHL-10 and HT) and 2 c-MYChigh/BCL2high DLBCL cell lines (DOHH2 and OCI-LY8) were used for in vitro assays. The prognostic impact of differential chemokine secretion and immune profiles was evaluated in a mouse tumor model. RNA-seq analysis revealed significantly higher CCL2 and CCR2 mRNA in DE DLBCLs (Padj < 0.05). Public datasets showed higher M2/macrophage ratio and lower T cell infiltration in DE DLBCLs (P < 0.05). Immunohistochemistry confirmed higher M2 macrophages and M2/total macrophage ratio in DE DLBCL (P=0.010 and P=0.098, respectively). In vitro, c-MYChigh/BCL2high cell lines exhibited increased CCL2 secretion, as seen in RNA-seq analysis. Knockdown and overexpression studies identified that MYC and BCL2 overexpression increased CCL2 secretion by upregulation of NF-κB p65 subunit, and the increased CCL2 secretion was crucial for M2 polarization. In mouse tumor models, CCL2 was related to aggressive tumor growth and an immunosuppressive tumor microenvironment. In conclusion, the increased CCL2/CCR2 axis confers aggressiveness of DE DLBCLs by increasing M2 polarization.
2024-09-30 | GSE252690 | GEO
Project description:Gene-level transcriptome analysis of monocyte mRNA derived from mice that are genetically deficient of the Ccl2 gene or Ccr2 gene The CCL2/CCR2 chemokine axis is critical in monocytes mobilization and innate immunity. Although mice deficient in either gene manifest similar phenotype, such as reduced atherosclerosis, some biologic processes are disrupted in starkly different ways in these mice. We found in a Her2/neu driven mammary carcinoma model, the absence of Ccl2 inhibits tumor growth and prolongs survival, while genetic deletion of Ccr2 has the opposite effect. One of the postulated mechanisms is that Ccl2 and Ccr2 affect monocyte development in different manners. This experiment was designed to compare the whole transcriptome of monocytes that are deficient in either Ccl2 or Ccr2, with the hypothesis that differential development of these monocytes will manifest as differential gene expression profiles.
2016-10-21 | GSE88962 | GEO
Project description:RNA-seq data for 6 de novo GCB subtype DLBCL patients with BCL2 translocation
2022-07-01 | GSE179689 | GEO
Project description:GCB subtype DLBCL with BCL2 translocation
| PRJNA744546 | ENA
Project description:Leukocyte recruitment, a universal feature of tissue inflammation, is regulated by the interactions of chemokines with their G protein-coupled receptors. Activation of CC chemokine receptor 2 (CCR2) by its cognate chemokine ligands, including CCL2, plays a central role in recruitment of monocytes in several inflammatory diseases. In this study, we used phosphoproteomics to enable unbiased characterization of the signaling network resulting from CCL2 activation of CCR2. Using data-independent acquisition (DIA) mass spectrometry, both the proteome and phosphoproteome were quantified for FlpIn-HEK293T cells stably expressing CCR2, at six time points after activation with CCL2, in comparison with untreated cells. Differential expression analysis identified 699 significantly regulated phosphorylation sites located on 441 proteins. As expected, many of these proteins participate in canonical signal transduction pathways and the regulation of actin cytoskeleton dynamics, including numerous guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). In addition, we identified regulated phosphorylation sites in numerous proteins that exert functions in the nucleus, including several constituents of the nuclear pore complex. This study provides an unprecedented level of detail about CCR2 signalling and identifies potential novel targets for regulation of CCR2 function.
2020-04-08 | PXD015845 | Pride
Project description:Monocytes have been categorized in three main subpopulations based on CD14 and CD16 surface expression. Classical monocytes are the most abundant subset in the blood. They express a CD14+CD16-CCR2+ phenotype, which confers on them the ability to migrate to inflammatory sites by quickly responding to CCL2 signaling. Here we identified and characterized the surge and expansion of a novel monocyte subset during SIV and HIV infection. They were undistinguishable from classical monocytes regarding CD14 and CD16 expression, but did not express surface CCR2. Transcriptome analysis of sorted cells confirmed that they represent a distinct subpopulation that expresses lower levels of inflammatory cytokines and activation markers than their CCR2+ counterparts. They exhibited impaired phagocytosis and deficient chemotaxis in response to CCL2 and CCL7, besides being refractory to SIV infection. We named these cells atypical CCR2- classical (ACC) monocytes, and believe they play an important role in AIDS pathogenesis, possibly reflecting an anti-inflammatory response against the extreme immune activation observed during SIV and HIV infection. Antiretroviral therapy caused this population to decline in both macaque and human subjects, suggesting that this atypical phenotype may be induced by viral replication. Expression profiling by NanoString nCounter gene expression system. Classical monocytes (CD14++CD16-) from six SIV-infected macaques (day 14 post inoculation) were sorted in two groups according to CCR2 expression.
2012-03-01 | E-GEOD-27559 | biostudies-arrayexpress
Project description:NIS-lncRNA promotes neuropathic pain by increasing Ccl2 expression
| PRJNA848831 | ENA
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:A number of inhibitors of chemokine CCL2 and its receptor CCR2 are in development and may find application for treating a range of inflammatory conditions, including autoimmune and viral arthritides. Herein we sought to determine the effect of CCR2 deficiency on arthritis caused by an arthritogenic alphavirus, Chikungunya virus. Chikungunya virus (LR2006-OPY1) was injected subcutaneously into the hind foot of either CCR2 knockout or wild-type control mice (n=4-6). At day 0 and d7 post infection, RNA from the feet was harvested, the RNA was pooled (4-6 feet per time point per mouse strain) and gene expression analysis was performed using Mouse Gene ST arrays (Affymetrix).
2014-04-23 | E-GEOD-56965 | biostudies-arrayexpress
Project description:Comparative analysis of FACS-sorted CCR2- and CCR2+ HSC in the steady state. CCR2+ HSC have fourfold higher proliferative rates than CCR2- HSC, are are biased towards the myeloid lineage and dominate the migratory HSC population. Comparison of pooled CCR2- and CCR2+ HSC (bone marrow from 20 mice pooled for each sample), three biological replicates each.
2015-05-01 | E-GEOD-53827 | biostudies-arrayexpress