Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA350787 | ENA |
REPOSITORIES: ENA
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Project description:Although diffuse large B-cell lymphoma (DLBCL) is a very heterogeneous disease, patients are as standard treated with a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). Since approximately 40% of patients die due to refractory disease or relapse, enhanced knowledge about drug response mechanisms is required to improve treatment outcome. Therefore, this study assesses parameters that possibly influence doxorubicin response. Doxorubicin-induced impact on the number of living cells was evaluated for four human DLBCL cell lines, illustrating differences in intrinsic sensitivity levels. Six cell lines were subjected to gene expression profiling upon exposure to two distinct drug concentrations (0.00061 μg/mL and 2.5 μg/mL) for 2, 12, and 48 hours. Variation in gene expression compared to baseline was determined with a mixed-effects model, and gene ontology enrichment analysis was performed using the webtools GOrilla and REVIGO. Only few genes were differentially expressed after short exposure and/or exposure to the low concentration, suggesting lack of drug efficacy under these conditions. In contrast, 12-hour exposure to the high concentration induced several changes. In sensitive cell lines, doxorubicin affected the expression of genes involved in ncRNA metabolism, DNA repair, and cell cycle process mechanisms. In resistant cell lines, the expression of genes implicated in metabolic processes were altered. Thus, we observed a differential response rate to doxorubicin in distinct DLBCL cell lines and demonstrated that doxorubicin-induced alterations in gene expression and resulting ontologies vary with drug concentration, exposure duration, and intrinsic sensitivity level.
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Project description:The standard treatment for patients with diffuse large B-cell lymphoma (DLBCL) is the immunochemotherapy-based R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone). Resistance to treatment, intrinsic or acquired, is observed in approximately 40% of patients with DLBCL, who thus require novel interventions to survive. To identify biomarkers for cytotoxic response assessment, microRNAs (miRNAs) associated with doxorubicin sensitivity were determined by combining global miRNA expression profiling with systematic dose-response screens in 15 human DLBCL cell lines. One candidate, miR-34a, was tested in functional in vitro studies and in vivo in a retrospective clinical cohort. High expression of miR-34a was observed in cell lines sensitive to doxorubicin, and upregulation of miR-34a is documented here to increase doxorubicin sensitivity in in vitro lentiviral transduction assays. High expression of miR-34a had a prognostic impact using overall survival as outcome. With risk stratification of DLBCL samples based on resistance gene signatures (REGS), doxorubicin-responsive samples had statistically significant upregulated miR-34a expression. Classification of the DLBCL samples into subset-specific B cell-associated gene signatures (BAGS) revealed differentiation-specific expression of miR-34a. Our data further support FOXP1 as a target of miR-34a, suggesting that downregulation of FOXP1 may sensitize DLBCL cells to doxorubicin. We conclude that miRNAs, in particular miR-34a, may have clinical utility in DLBCL patients as both predictive and prognostic biomarkers.
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Project description:Canine lymphoma is the most common hematological cancer in dogs and shares many molecular and clinical characteristics with human Non-Hodgkin lymphoma (NHL). The standard treatment for canine lymphoma is the “CHOP” sequential multiagent chemotherapy protocol consisting of Cyclophosphamide, Doxorubicin (Hydroxydaunorubicin), Vincristine (Oncovin™), and Prednisone. Approximately 70 - 85% of patients treated with CHOP achieve clinical remission. However, duration of remission varies and the majority of dogs eventually relapse. To identify possible biomarkers for patients failing to achieve remission in response to CHOP, we performed RNA-Seq analysis on 25 cases of canine lymphoma taken at the start of their CHOP therapy regime, and determined patient progression free survival (PFS).
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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.
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Project description:This SuperSeries is composed of the following subset Series: GSE21846: Transcriptional profiling of 29 cases of diffuse large B cell lymphoma GSE21847: miRNA profiling of 29 cases of diffuse large B cell lymphoma GSE21848: miRNA profiling of 36 cases of diffuse large B cell lymphoma Refer to individual Series
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