GEO accession GSE262641 is currently private and is scheduled to be released on May 30, 2025.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1092687 | ENA |
REPOSITORIES: ENA
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Project description:Diffuse large B-cell lymphoma (DLBCL) is an aggressive, heterogeneous disease with poor prognosis associated with high-risk molecular features. We report the discovery of golcadomide (CC-99282), a novel cereblon-modulating agent, that induces faster and deeper degradation of hematopoietic transcription factors Ikaros/Aiolos compared with first-generation degraders such as lenalidomide. In vitro, golcadomide induced interferon-stimulated genes, promoted apoptosis, robust antiproliferation, and immunogenic cell death, independent of clinical outcome determinators observed with standard care treatment. In vivo, golcadomide exhibited enhanced antitumor activity, resulting in significant tumor regression and tumor-free animals in lymphoma xenograft models. Pharmacological and CRISPR-based screenings demonstrated that targeting apoptosis, cell cycle progression, NF-kB signaling, and nuclear cytoplasmic transport increased antitumor efficacy of golcadomide. In summary, these data represent the discovery of golcadomide as a promising drug candidate for DLBCL and highlight the rationales for future golcadomide-based combination regimens that could improve clinical outcomes for patients.
2025-10-10 | GSE262641 | GEO
Project description:CC-122 is a next-generation cereblon E3 ligase modulating agent that has demonstrated promising clinical efficacy in relapsed or refractory diffuse large B‐cell lymphoma (R/R DLBCL) patients. Mechanistically, CC-122 induces the degradation of IKZF1/3, leading to T cell activation and robust cell-autonomous killing in DLBCL. Here, we report a genome-wide CRISPR/Cas9 positive selection screen for CC-122 in a DLBCL cell line SU-DHL-4 with follow-up mechanistic characterization in 6 DLBCL cell lines to identify genes regulating the response to CC-122. Top-ranked CC-122 resistance genes encode not only well-defined members or regulators of the CUL4-DDB1-RBX1-CRBN E3 ubiquitin ligase complex, but also key components of several signaling and transcriptional networks that have not previously been shown to modulate the response to other cereblon modulators. Ablation of CYLD, NFKBIA, TRAF2, or TRAF3 induces hyper-activation of the canonical and/or non-canonical NF-κB pathways and subsequently diminishes CC-122-induced apoptosis in 5 out of 6 DLBCL cell lines. Depletion of KCTD5, the substrate receptor of the CUL3-RBX1-KCTD5 ubiquitin ligase complex, promotes the stabilization of its cognate substrate, GNG5, resulting in CC-122 resistance in HT, SU-DHL-4, and WSU-DLCL2. Furthermore, knockout of AMBRA1 renders resistance to CC-122 in SU-DHL-4 and U-2932, whereas knockout of RFX7 leads to resistance specifically in SU-DHL-4. The ubiquitous and cell line-specific mechanisms of CC-122 resistance in DLBCL cell lines revealed in this work pinpoint genetic alternations that are potentially associated with clinical resistance in patients, and facilitate the development of biomarker strategies for patient stratification, which may improve clinical outcome of CC-122 for R/R DLBCL.
2020-10-01 | GSE158303 | GEO
Project description:Cereblon (CRBN), a substrate receptor of the E3 ubiquitin ligase complex CRL4CRBN, is the target of the immunomodulatory drugs lenalidomide and pomalidomide. Recently, it was demonstrated that binding of these drugs to CRBN promotes the ubiquitination and subsequent degradation of two common substrates, transcription factors Aiolos and Ikaros. Here we report that the pleiotropic pathway modifier CC-122, a new chemical entity termed pleiotropic pathway modifier binds CRBN and promotes degradation of Aiolos and Ikaros in diffuse large B-cell lymphoma (DLBCL) and T cells in vitro, in vivo and in patients, resulting in both cell autonomous as well as immunostimulatory effects. In DLBCL cell lines, CC-122-induced degradation or shRNA mediated knockdown of Aiolos and Ikaros correlates with increased transcription of interferon stimulated genes (ISGs) independent of interferon α, β, γ production and/or secretion and results in apoptosis in both ABC and GCB-DLBCL cell lines. Our results provide mechanistic insight into the cell of origin independent anti-lymphoma activity of CC-122, in contrast to the ABC subtype selective activity of lenalidomide. Microarray analysis of the OCI-LY10 activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) cell line treated with the compound CC-122 for 18 hours
2015-11-26 | E-GEOD-75420 | biostudies-arrayexpress
Project description:Cereblon (CRBN), a substrate receptor of the E3 ubiquitin ligase complex CRL4CRBN, is the target of the immunomodulatory drugs lenalidomide and pomalidomide. Recently, it was demonstrated that binding of these drugs to CRBN promotes the ubiquitination and subsequent degradation of two common substrates, transcription factors Aiolos and Ikaros. Here we report that the pleiotropic pathway modifier CC-122, a new chemical entity termed pleiotropic pathway modifier binds CRBN and promotes degradation of Aiolos and Ikaros in diffuse large B-cell lymphoma (DLBCL) and T cells in vitro, in vivo and in patients, resulting in both cell autonomous as well as immunostimulatory effects. In DLBCL cell lines, CC-122-induced degradation or shRNA mediated knockdown of Aiolos and Ikaros correlates with increased transcription of interferon stimulated genes (ISGs) independent of interferon α, β, γ production and/or secretion and results in apoptosis in both ABC and GCB-DLBCL cell lines. Our results provide mechanistic insight into the cell of origin independent anti-lymphoma activity of CC-122, in contrast to the ABC subtype selective activity of lenalidomide.
2015-11-26 | GSE75420 | GEO
Project description:Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, has a high degree of clinical and biological heterogeneity. Although most patients can be cured with R-CHOP immunochemotherapy,30-40% of patients have progression or recurrence after treatment. Therefore, there is an urgent need to find new treatments to improve the survival rate of this group of patients. Natural small molecule drugs have unique advantages as anticancer agents due to their low toxicity and multiple targets. This project aims to explore potentially effective natural compounds as new therapeutic strategies for DLBCL. We found that Cinobufagin is a potentially effective therapeutic agent for DLBCL. Glucose 6 phosphate dehydrogenase (G6PD), a risk factor for poor prognosis in DLBCL, was a direct target of Cinobufagin. By inhibiting the enzyme activity of G6PD, Cinobufagin could inhibit DNA synthesis and the production of reductive NADPH, thereby inducing ROS accumulation and apoptosis of DLBCL cells. Our findings provide new strategies for the treatment of DLBCL.
2024-07-31 | GSE254385 | GEO
Project description:RC-DLBCL (Diffuse Large-B Cell Lymphomas)
| PRJNA1311170 | ENA
Project description:Biomarker study for a phase 1, Open-Label, multicenter trial of azacitidine (CC-486) plus R-CHOP in subjects with high-risk previously untreated diffuse large B-cell lymphoma
2022-06-29 | GSE157302 | GEO
Project description:Diffuse large B-cell lymphoma (DLBCL) is currently divided into three main molecular subtypes, defined by gene expression profiling (GEP): Germinal Center B-cell like (GCB), Activated B-Cell like (ABC), and Primary Mediastinal B-cell Lymphoma (PMBL). DLBCL subtypes were determined according to patients' gene expression profiles.
2017-01-30 | GSE87371 | GEO
Project description:Analysis of diffuse large B-cell lymphoma (DLBCL) from primary sites (named as S1, S2 and S3) and metastatic lymph nodes (named as L1, L2 and L3). Results provide insight into the targets involved in t DLBCL dissemination.
2017-06-30 | GSE81968 | GEO
Project description:We performed a veterinary clinical oncology trial in client-owned dogs to determine if immune modulating drugs could be combined in rational approaches to treat spontaneous canine diffuse large B cell lymphoma (DLBCL).
2023-08-29 | GSE213088 | GEO