Gene expression of 61 FFPE tissues of DLBCL patients at high-risk (aaIPI 2 or 3)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE156309 | GEO | 2023/08/16
REPOSITORIES: GEO
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Project description:Diffuse large B-cell lymphoma (DLBCL), the most common aggressive non-Hodgkin lymphoma, demonstrates significant molecular heterogeneity and suboptimal clinical outcomes. Notably, 10%-15% of patients develop primary refractory disease following first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) regimen. While epigenetic modulators have emerged as potential therapeutic options for these high-risk cases, clinical application of broad-spectrum DNA methyltransferase inhibitors such as decitabine and azacitidine remains limited by their multi-target toxicity profiles. In this study, we demonstrated that DNA methyltransferase 1 (DNMT1) plays a critical oncogenic role in DLBCL pathogenesis.
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Project description:Diffuse large B-cell lymphoma (DLBCL), the most common aggressive non-Hodgkin lymphoma, demonstrates significant molecular heterogeneity and suboptimal clinical outcomes. Notably, 10%-15% of patients develop primary refractory disease following first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) regimen. While epigenetic modulators have emerged as potential therapeutic options for these high-risk cases, clinical application of broad-spectrum DNA methyltransferase inhibitors such as decitabine and azacitidine remains limited by their multi-target toxicity profiles. In this study, we demonstrated that DNA methyltransferase 1 (DNMT1) plays a critical oncogenic role in DLBCL pathogenesis.
2025-04-13 | GSE290802 | GEO
Project description:Rituximab alone or in combination with chemotherapeutics is the first-line therapy for variety of lymphoproliferative disorders including low- and high grade non-Hodgkin’s lymphomas (NHL). Although the complete response rate is quite impressive, vast majority of patient presents recurrent disease. The association between CD20 expression and clinical outcome in patients strongly suggests that reduced CD20 expression leads to inferior response to RCHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone). In order to understand how loss of CD20 leads to development of RCHOP resistance, we developed rituximab resistant DOHH2 model in vivo by chronic exposure to rituximab. Characterization of several resistant in vivo xenografts revealed one model that maintained resistance to an acute dose of rituximab and demonstrated loss of CD20. Further characterization of the model demonstrated a loss of CD20 is associated with over expression of BCL2 and BIM. In vivo efficacy studies showed resistant line is insensitive to acute dose of RCHOP and treatment with an inhibitor of BCL2 (ABT199) in combination with chemotherapy resulted in better efficacy than RCHOP alone. We have identified an in vivo model of DLBCL where loss of CD20 and over expression of anti-apoptotic protein BCL2 leads to RCHOP resistance. These data suggest the addition of BCL2 inhibitor to chemotherapy might be effective in treating CD20 negative lymphomas. mRNA profiles of parental and rituximab resistant DOHH2 xenograft were generated by deep sequencing using Illumina HiSeq
2014-09-01 | E-GEOD-54201 | biostudies-arrayexpress
Project description:We used gene expression profiling and pathway impact analyses to search signaling pathways, which mediate crosstalk between lymphoma cells and tumor-infiltrating inflammatory cells and contribute to the outcome of follicular lymphoma (FL) patients. 24 FL patients treated with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy were classified into groups of favorable or adverse outcomes, and the transcripts differentially expressed in the pretreatment FL tissues between the groups were analyzed.
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Project description:Rituximab alone or in combination with chemotherapeutics is the first-line therapy for variety of lymphoproliferative disorders including low- and high grade non-Hodgkin’s lymphomas (NHL). Although the complete response rate is quite impressive, vast majority of patient presents recurrent disease. The association between CD20 expression and clinical outcome in patients strongly suggests that reduced CD20 expression leads to inferior response to RCHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone). In order to understand how loss of CD20 leads to development of RCHOP resistance, we developed rituximab resistant DOHH2 model in vivo by chronic exposure to rituximab. Characterization of several resistant in vivo xenografts revealed one model that maintained resistance to an acute dose of rituximab and demonstrated loss of CD20. Further characterization of the model demonstrated a loss of CD20 is associated with over expression of BCL2 and BIM. In vivo efficacy studies showed resistant line is insensitive to acute dose of RCHOP and treatment with an inhibitor of BCL2 (ABT199) in combination with chemotherapy resulted in better efficacy than RCHOP alone. We have identified an in vivo model of DLBCL where loss of CD20 and over expression of anti-apoptotic protein BCL2 leads to RCHOP resistance. These data suggest the addition of BCL2 inhibitor to chemotherapy might be effective in treating CD20 negative lymphomas.
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Project description:A "Cartes d'Identite des Tumeurs" (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net). 53 samples hybridized on Affymetrix HG-U133A GeneChips arrays, for 53 patients with diffuse large B-cell lymphoma (DLBCL); patients are treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or Ritxumab (R)-CHOP in the Groupe dB^REtude des Lymphomes de lB^RAdulte (GELA) clinical centers.
2008-06-01 | E-TABM-346 | biostudies-arrayexpress
Project description:Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves, including cell-of-origin, genomic alterations, and gene/protein expressions. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using highly-sensitive transcriptome profiling of untreated DLBCL tissues, we here assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells, in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of “unfavorable” molecular signatures.
2021-06-18 | GSE178394 | GEO
Project description:Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves, including cell-of-origin, genomic alterations, and gene/protein expressions. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using highly-sensitive transcriptome profiling of untreated DLBCL tissues, we here assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells, in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of “unfavorable” molecular signatures.
2021-09-01 | GSE178965 | GEO
Project description:Despite recent therapeutic improvements, the clinical course of diffuse large B-cell lymphoma (DLBCL) still differs considerably among patients. We conducted this retrospective multi-centre study to evaluate the impact of genomic aberrations detected using a high-density genome wide-single nucleotide polymorphism-based array on clinical outcome in a population of DLBCL patients treated with R-CHOP-21 (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21 d). 167 DNA samples were analysed using the GeneChip Human Mapping 250K NspI. Genomic anomalies were analysed regarding their impact on the clinical course of 124 patients treated with R-CHOP-21. Unsupervised clustering was performed to identify genetically related subgroups of patients with different clinical outcomes. Twenty recurrent genetic lesions showed an impact on the clinical course. Loss of genomic material at 8p23.1 showed the strongest statistical significance and was associated with additional aberrations, such as 17p- and 15q-. Unsupervised clustering identified five DLBCL clusters with distinct genetic profiles, clinical characteristics and outcomes. Genetic features and clusters, associated with a different outcome in patients treated with R-CHOP, have been identified by arrayCGH. DNA copy number profiling by SNP array.
2009-04-01 | GSE15127 | GEO
Project description:Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoid neoplasm in the world representing 30-40% of all lymphomas. Standard immunochemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab) ensures cure in 60 to 65% of patients, while the rest progress or relapse. While advances have been made in the treatment of DLBCL, especially with the addition of rituximab, it is now apparent that there may be significant differences in prognosis that are related to the cell of origin, and that this disease is heterogeneous and novel treatment options are needed. It has been hypothesized that the combination of HDACI and hypomethylating agents might be a new approach to the treatment of relapsed or refractory DLBCL. This combination is thought to disrupt the transcription repressor complex consisting of methyl binding domain proteins (MBDP) and histone deacetylases (HDACs). We have explored the effect of different HDACI and decitabine combinations in in vitro and in vivo models of DLBCL. These data suggest a class effect, with all four HDACI (panobinostat, belinostat, vorinostat, depsipeptide) synergizing with decitabine in cytotoxicity assay across the spectrum of DLBCL cells. Synergy was validated in a number of other assays including a caspase 3 activation and apoptosis. Furthermore, the combination of panobinostat and decitabine induced markedly increased histone acetylation. The in vitro observations were confirmed in an in vivo murine xenograft experiment with the Ly1 DLBCL line. Genome wide methylation analysis and gene expression profiling demonstrated that the combination of these two epigenetic therapies produced a unique gene expression profile compared to the samples treated with single drugs. These data strongly support the potential therapeutic role of a combinatorial epigenetic platform for the treatment of B-cell lymphomas, in particular in patients with DLBCL. Clearly, future studies will need to focus on integrating the appropriate correlative studies, with an effort to identify and or validate biomarkers of activity with these combinations. The likelihood moving forward is that the mechanism of action of these combinations may vary from disease context to disease context. Genome-wide array findings from these kinds of studies could be expanded to samples from patients on clinical trials to identify novel biomarkers of response, leading to the rational treatment of individual diseases based upon the underlying pathogenesis. We have used single samples from three DLBCL cell lines (biological replicates) which were treated with DMSO, decitabine alone, panobinostat alone and their combination for 48h - total of 12 samples
2011-02-15 | E-GEOD-27226 | biostudies-arrayexpress