Large B-cell lymphoma imprints dysfunctional immune phenotype that persists years after treatment
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ABSTRACT:
PROVIDER: PRJEB80155 | ENA |
REPOSITORIES: ENA
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Project description:Comprehensive study of the immune fingerprint of lymphoma and immunotherapy on DLBCL survivors
2025-09-01 | GSE277575 | GEO
Project description:Large B-cell lymphoma imprints dysfunctional immune phenotype that persists years after treatment
| PRJNA1162855 | 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:We aimed to characterize the long-term health outcomes of survivors of severe acute respiratory syndrome (SARS) and determine their recovery status and possible immunological basis. Although health outcomes continued to improve, SARS survivors still suffered from physical fatigue, osteoporosis, and necrosis of the femoral head 18 years after discharge, possibly related to plasma metabolic disorders and immunological alterations.
2023-09-06 | GSE216357 | GEO
Project description:Many cancer survivors suffer from impairments in skeletal muscle (SkM), both in terms of reduced mass and function. Interestingly, human SkM possesses an epigenetic memory of earlier stimuli, such as exercise. Long-term retention of epigenetic changes in SkM following cancer survival and/or exercise training have not yet been studied. We therefore investigated genome-wide DNA methylation (the methylome) in SkM following a 5-month, 3/week treadmill-based aerobic training intervention in breast cancer survivors 10-14 years after diagnosis and treatment. These results were compared to breast cancer survivors who remained untrained and to age-matched controls with no history of cancer, who undertook the same training intervention. SkM biopsies were obtained before (pre) and after (post) the 5-month training period and DNA methylation was analysed using InfiniumEPIC 850K Arrays. The breast cancer survivors displayed a significant retention of increased DNA methylation (i.e., hypermethylation) at a larger number of differentially methylated positions (DMPs) compared with healthy age-matched controls pre-training. Training in cancer survivors led to an exaggerated number of DMPs with a hypermethylated signature occurring at more random non-regulatory regions across the DNA compared with training in healthy age-matched controls. However, the opposite occurred in important gene regulatory regions, where training in cancer survivors elicited a considerable reduction in methylation (i.e., hypomethylation) in 99% of the DMPs located specifically in CpG islands within promoter regions. Importantly, training was able to reverse the hypermethylation identified in cancer survivors back towards a hypomethylated signature that was observed pre-training in healthy age-matched controls at 300 (out of 881) of these island and promoter associated CpG sites. Pathway enrichment analysis identified that the training in cancer survivors evoked this predominantly hypomethylated signature in pathways associated with: Cell cycle, DNA replication and repair, transcription, translation, mTOR signalling and proteosome. Differentially methylated region (DMR) analysis also identified genes: BAG1, BTG2, CHP1, KIFC1, MKL2, MTR, PEX11B, POLD2, S100A6, SNORD104 and SPG7 as hypermethylated in breast cancer survivors with training reversing these CpG island / promoter associated DMRs towards a hypomethylated signature. Training also elicited a largely different epigenetic response in healthy individuals than that observed in cancer survivors, with very few overlapping changes. Only one gene, SIRT2, was identified as having altered methylation in cancer survivors at baseline as well as after training in both the cancer survivors and healthy controls. In conclusion, human SkM muscle retains a hypermethylated signature for as long as 10-14 years after breast cancer treatment and survival. Importantly, 5 months of aerobic training rejuvenated the SkM methylome towards signatures identified in healthy age-matched individuals in gene regulatory regions.
2022-09-12 | GSE213029 | GEO
Project description:Molecular pathogenesis of posttransplant (PT) lymphoproliferative disorder, including the most prevalent diffuse large B cell lymphoma (DLBCL), is largely unknown. We have recently showed that Epstein-Barr Virus (EBV)+ and EBV- PT-DLBCL are biologically different, but gene expression profile of the latter lymphoma is similar to that of immunocompetent (IC) DLBCL. To validate these findings on a genomic level, we performed array CGH analysis of 21 EBV+ and 6 EBV- PT-DLBCL, and 11 control IC-DLBCL. Genomic and transcriptomic data were subsequently integrated. Notably, EBV+ and EBV- PT-DLBCL revealed only one shared recurrent imbalance, while EBV- PT-DLBCL displayed at least 10 aberrations recurrent in IC-DLBCL, among others gain of 3/3q and 18q, and loss of 6q23/TNFAIP3 and 9p21/CDKN2A. EBV+ PT-DLBCL showed distinct aberrations, including the most prevalent gain/amplification of 9p24.1 targeting PDCD1LG2/PDL2. Significant differential representation/expression of 3p13/FOXP1 and 9p21/CDKNA2 in EBV+ PT-DLBCL when compared with EBV- PT-/IC-DLBCL, suggests that the oncogene FOXP1 and the tumor suppressor gene CDKNA2 are not implicated in pathogenesis of EBV+ PT-DLBCL. In summary, genomic profiling of PT-/IC-DLBCL confirmed biological distinctness of EBV+ and EBV- PT-DLBCL, and relationship between EBV- PT-DLBCL and IC-DLBCL. These findings support the hypothesis that EBV- PT-DLBCL are coincidental lymphomas in transplant recipients
2015-06-02 | GSE69440 | GEO
Project description:Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumors. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumors of DLBCL patients, apparently reflecting the variation in tumor proliferation rate, host response and differentiation state of the tumor. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal center B cells ('germinal center B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal center B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumors on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer. This study is described more fully in Alizadeh AA et al.(2000) Nature 403:503-11
2002-06-27 | E-GEOD-60 | biostudies-arrayexpress
Project description:Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumors. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumors of DLBCL patients, apparently reflecting the variation in tumor proliferation rate, host response and differentiation state of the tumor. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal center B cells ('germinal center B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal center B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumors on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer. This study is described more fully in Alizadeh AA et al.(2000) Nature 403:503-11 Keywords: other
2002-06-27 | GSE60 | GEO
Project description:Treatment of diffuse large B-cell lymphoma (DLBCL) remains challenging due to extensive molecular, clinical, and pathological heterogeneity. Here, we report recurrent focal deletions of the chr14q32.31-32 locus, including TRAF3, a negative regulator of NF-κB signaling, in a cohort of uniformly-treated de novo DLBCL (24/324 cases). Integrative analysis uncovered a correlation between TRAF3 copy number loss and TRAF3 reduced expression. CRISPR-mediated TRAF3 loss-of-function (LOF) in DLBCL cell lines enhanced non-canonical NF-κB (NC NF-κB) signaling, rendering cells sensitive to shRNA-induced knockdown of the central NC NF-κB kinase, NIK. NIK pharmacological inhibitors differentially impaired proliferation, and induced apoptosis of TRAF3 LOF cells, further suggesting an acquired onco-addiction to NC NF-κB. Beyond these cell-intrinsic effects, co-culturing of TRAF3 LOF DLBCL cells with primary human CD8+ T-cells revealed an impairment in effector marker induction (Granzyme B, IFNγ) and proliferation in the latter. Accordingly, a reduction in T-cell infiltrates was observed in the microenvironment of TRAF3-low expressing primary DLBCL tumor samples. Neutralization of IL10 produced by TRAF3 LOF cells restored and enhanced GZMB and IFNγ expression in co-cultured CD8+ T-cells. Our findings demonstrate a direct relationship between TRAF3 genetic alterations and NC NF-κB activation, favoring pro-oncogenic cell-intrinsic effects and immune-evasive mechanisms, and highlight NIK as a therapeutic target in defined subset of DLBCL.
2024-04-11 | GSE218750 | 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