Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA341450 | ENA |
REPOSITORIES: ENA
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Project description:Mantle cell lymphoma (MCL) accumulates in lymphoid organs but disseminates early on in extranodal tissues. Although proliferation remains located in lymphoid organs only, suggesting a major role of the tumor ecosystem, few studies have assessed MCL microenvironment. We therefore cocultured primary circulating MCL cells from 21 patients several weeks ex vivo with stromal or lymphoid-like (CD40L) cells to determine which interactions could support proliferation of MCL cells. We showed that coculture with lymphoid-like cells, but not stromal cells, induced cell-cycle progression, which was amplified by MCL-specific cytokines (IGF-1, BAFF, IL-6, IL-10). Of interest, we showed that our model recapitulated the MCL in situ molecular signatures i.e., proliferation, NFkB and survival signatures. We further demonstrated that proliferating MCL harbored an imbalance in Bcl-2 family expression leading to a consequent loss of mitochondrial priming. Interestingly, this loss of priming was overcome by the Type II anti-CD20 antibody obinutuzumab, which counteracted Bcl-xL induction through NFkB inhibition. Finally, we showed that the mitochondrial priming directly correlated with the sensitivity toward venetoclax and alkylating drugs. By identifying the microenvironment as the major support for proliferation and drug resistance in MCL, our results highlight a selective approach to target the lymphoma niche.
2017-01-02 | GSE86322 | GEO
Project description:We investigated the differential regulation patterns of type I anti-CD20 monoclonal antibody (mAb) rituximab and type II obinutuzumab on a transcriptional level. Using a panel of MCL cell lines, we determined the effects of obinutuzumab and rituximab as monotherapies as well as in combination on cell viability and proliferation. Obinutuzumab induced a higher reduction in cell proliferation in each mantle cell lymphoma cell line than rituximab did. Results indicate a common pattern of expression changes after binding of anti-CD20 mAbs, but also reveal a significant difference between type I and type II treatment. Combination treatment resulted in a rituximab-like expression pattern. Many deregulated genes were associated with stress signalling, cell death, immune response and other functional clusters. Our analyses identified different and antibody-specific downstream expression patterns of obinutuzumab and rituximab, which may represent the molecular basis of the superior effect of obinutuzumab in comparison to rituximab.
2014-12-31 | GSE54169 | GEO
Project description:The microenvironment strongly influences mantle cell lymphoma (MCL) survival, proliferation and chemoresistance. However, little is known regarding the molecular characterization of lymphoma niches. We focused on the interplay between MCL cells and associated monocytes/macrophages.
2019-08-27 | GSE124931 | GEO
Project description:Our investigation uncovers that nanomolar concentrations of salinomycin, monensin, nigericin, and narasin (a group of potassium/sodium cation carriers) robustly enhance surface expression of CD20 antigen in B-cell-derived tumor cells, including primary malignant cells of chronic lymphocytic leukemia and diffuse large B-cell lymphoma. Experiments in vitro, ex vivo, and animal model reveal a novel approach of combining salinomycin or monensin with therapeutic anti-CD20 monoclonal antibodies or anti-CD20 CAR-T cells, significantly improving non-Hodgkin lymphoma (NHL) therapy. The results of RNA-seq, genetic editing, and chemical inhibition delineate the molecular mechanism of CD20 upregulation, at least partially, to the downregulation of MYC, the transcriptional repressor of the MS4A1 gene encoding CD20. Our findings propose the cation carriers as compounds targeting MYC oncogene, which can be combined with anti-CD20 antibodies or adoptive cellular therapies to treat NHL and mitigate resistance, which frequently depends on the CD20 antigen loss, offering new solutions to improve patient outcomes.
2025-07-09 | GSE282862 | GEO
Project description:We report the single-cell RNA sequencing data obtained from BCL1 lymphoma-bearing mice treated with either isotype control, anti-CD20 mAb, anti-CD27 mAb or anti-CD20+anti-CD27 mAb together
2018-01-12 | GSE97037 | GEO
Project description:The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma Keywords: lymphochip; MCL; untreated Tumor biopsies from 71 untreated patients with mantle cell lymphoma
2010-05-23 | E-GEOD-10793 | biostudies-arrayexpress
Project description:Drug-tolerant “persister” tumor cells underlie the emergence of drug-resistant clones contribute to relapse and disease progression; thus, identifying actionable targets that disable persisters and mitigate relapse are a high priority need. Although the BCL2-targeting agent venetoclax (ABT-199) has shown promising responses in mantle cell and double hit B cell lymphomas, resistance often arises, yet mechanistically how this occurs is unclear. Here we report that ABT-199 resistance can evolve from persister clones that have selective deletions at 18q21 that involve the drug target BCL2 and the apoptotic regulators Noxa (PMAIP1) and TCF4. Notably, reprogramming of super enhancers (SE) in persisters contributes to resistance, where there is a selection for SE-directed overexpression of the apoptotic regulator BCL2A1 and oncogenic transcription factors IKZF1 and FOXC1. At the same time, the SE reprogramming confers an opportunity for overcoming ABT-199 resistance. An unbiased drug screen on a platform that recapitulates the lymphoma microenvironment revealed that persisters are vulnerable to inhibitors of transcription initiation and elongation, and especially so to inhibitors of cyclin-dependent kinase 7 (CDK7) that is essential for transcription initiation. Specifically, CDK7 loss or inhibition eliminated the persister phenotype by disabling SE-driven expression of BCL2A1, IKZF1 and FOXC1. Thus, the co-treatment of ABT-199 with CDK7 inhibitors blocked the evolution of drug resistance, and provoked tumor regression in models of mantle cell lymphoma (MCL) and double hit lymphomas (DHL) that overexpress both MYC and BCL2. Together, these findings establish loss of apoptotic regulators and an adaptive transcriptional response as drug resistance mechanisms in lymphoma, more importantly, establish a rationale for transcription inhibition-based combination strategies to prevent and overcome drug resistance in B cell malignancies toward BCL2 inhibitor.
2020-05-26 | PXD010193 | Pride
Project description:An LC-MS/MS based phosphoproteomics study that characterizes the signaling processes downstream of the B-cell receptor and how they are differentially regulated following treatment with anti-CD20 monoclonal antibodies in B-cell lymphoma.
2021-09-09 | PXD023572 | Pride
Project description:Primary Mediastinal large B-cell lymphoma (PMBL) is a rare form of non-Hodgkin lymphoma (NHL) representing 2% of mature B-cell NHL in patients less than 18 years of age.We compared the gene expression profiling between fully humanized anti-CD20 targeted monoclonal antibody recognizing a unique CD20 type II epitope, obinutuzumab and IgG or PBS treated Karpas Primary Mediastinal B-cell lymphoma (PMBL) cell line. -
2016-12-01 | GSE75605 | GEO
Project description:The covalent Bruton’s Tyrosine Kinase (BTK) inhibitor ibrutinib is highly efficacious against multiple B-cell malignancies. However, it also has off-target effects and multiple mechanisms of resistance, including the C481S mutation. We hypothesized that small molecule-induced BTK degradation might be able to overcome some of the limitations of traditional enzymatic inhibitors. Here, we demonstrate that BTK degradation results in more durable suppression of signaling and proliferation in cancer cells than BTK inhibition and that BTK degraders are able to efficiently degrade BTK C481S. Moreover, we generated DD-03-171, an optimized lead compound that exhibits enhanced anti-proliferative effects on mantle cell lymphoma (MCL) cells in vitro as well as efficacy in a patient-derived xenograft model of MCL. These data suggest that targeted BTK degradation is an effective therapeutic approach in treating MCL and overcoming ibrutinib resistance, thereby addressing a major unmet need in the treatment of MCL and other B-cell lymphomas.
2019-01-25 | PXD010568 | Pride