Transcriptional responses of mantle cell lymphoma (MCL) lines to IKKB inhibition
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE52434 | GEO | 2013/12/01
SECONDARY ACCESSION(S): PRJNA228924
REPOSITORIES: GEO
Similar Datasets
Project description:MCL cell lines were treated with DMSO or 5uM AFN700 for 20hrs This experiment is designed to see if NFKB-target genes are downregulated by inhibition of IKKB in MCL cell lines that are insensitive to ibrutinib (BTK inhibitor) or sotrastaurin (PKC inhibitor) MCL cells were seeded in 6well dishes and treated for 20hrs with DMSO or 5uM AFN700
2013-12-01 | E-GEOD-52434 | biostudies-arrayexpress
Project description:To determine the global transcriptome changes in mantle cell lymphoma cells following treatment with the BET bromodomain antagonist, JQ1 Mantle Cell Lymphoma (MCL) cells exhibit increased B cell receptor and NFkB activities. The BET protein BRD4 is essential for the transcriptional activity of NFkB. Here, we demonstrate that treatment with the BET protein bromodomain antagonist (BA) JQ1 attenuates MYC and CDK4/6, inhibits the nuclear RelA levels and the expression of NFκB target genes including Brutonâs Tyrosine Kinase (BTK) in MCL cells. While lowering the levels of the anti-apoptotic BCL2 family proteins, BA treatment induces the pro-apoptotic protein BIM and exerts dose-dependent lethality against cultured and primary MCL cells. Co-treatment with BA and the BTK inhibitor ibrutinib synergistically induces apoptosis of MCL cells. Compared to each agent alone, co-treatment with BA and ibrutinib markedly improved the median survival of mice engrafted with the MCL cells. BA treatment also induced apoptosis of the in vitro isolated, ibrutinib-resistant MCL cells which overexpress CDK6, BCL2, Bcl-xL, XIAP and AKT, but lack ibrutinib resistance-conferring BTK mutation. Co-treatment with BA and panobinostat (pan-histone deacetylase inhibitor) or palbociclib (CDK4/6 inhibitor) or ABT-199 (BCL2 antagonist) synergistically induced apoptosis of the ibrutinib-resistant MCL cells. These findings highlight and support further in vivo evaluation of the efficacy of the BA-based combinations with these agents against MCL, including ibrutinib-resistant MCL. MO2058 cells treated with vehicle, 250 nM or 1000 nM JQ1 for 8 hours. Samples were acquired and analyzed in duplicate.
2015-12-31 | E-GEOD-70651 | biostudies-arrayexpress
Project description:To determine the global transcriptome changes in mantle cell lymphoma cells following treatment with the BET bromodomain antagonist, JQ1 Mantle Cell Lymphoma (MCL) cells exhibit increased B cell receptor and NFkB activities. The BET protein BRD4 is essential for the transcriptional activity of NFkB. Here, we demonstrate that treatment with the BET protein bromodomain antagonist (BA) JQ1 attenuates MYC and CDK4/6, inhibits the nuclear RelA levels and the expression of NFκB target genes including Bruton’s Tyrosine Kinase (BTK) in MCL cells. While lowering the levels of the anti-apoptotic BCL2 family proteins, BA treatment induces the pro-apoptotic protein BIM and exerts dose-dependent lethality against cultured and primary MCL cells. Co-treatment with BA and the BTK inhibitor ibrutinib synergistically induces apoptosis of MCL cells. Compared to each agent alone, co-treatment with BA and ibrutinib markedly improved the median survival of mice engrafted with the MCL cells. BA treatment also induced apoptosis of the in vitro isolated, ibrutinib-resistant MCL cells which overexpress CDK6, BCL2, Bcl-xL, XIAP and AKT, but lack ibrutinib resistance-conferring BTK mutation. Co-treatment with BA and panobinostat (pan-histone deacetylase inhibitor) or palbociclib (CDK4/6 inhibitor) or ABT-199 (BCL2 antagonist) synergistically induced apoptosis of the ibrutinib-resistant MCL cells. These findings highlight and support further in vivo evaluation of the efficacy of the BA-based combinations with these agents against MCL, including ibrutinib-resistant MCL.
2015-12-31 | GSE70651 | GEO
Project description:Inhibition of BCR signaling through BTK inhibitor, ibrutinib, has generated a remarkable response in mantle cell lymphoma (MCL). However, approximately one-third of the patients do not respond well to the drug and disease relapse on ibrutinib is nearly universal. Alternative therapeutic strategies aimed to prevent and overcome ibrutinib resistance are needed. We compared and contrasted the effects of selinexor, a selective inhibitor of nuclear export, with ibrutinib in six MCL cell lines that display differential intrinsic sensitivity to ibrutinib. We found that selinexor had a broader anti-tumor activity in MCL than ibrutinib. MCL cell lines resistant to ibrutinib remained sensitive to selinexor. We showed that selinexor induced apoptosis/cell cycle arrest and XPO-1 knockdown also retarded cell growth. Further, down-regulation of the NF-B gene signature, as opposed to BCR signature, was a common feature that underlies the response of MCL to both selinexor and ibrutinib. Meanwhile, unaltered NF-B was associated with ibrutinib resistance. Mechnistically, selinexor induced nuclear retention of IB that was accompanied by the reduction of DNA binding activity of NF-B suggesting that NF-B is trapped in an inhibitory complex. Co-immunoprecipitation confirmed that p65 of NF-B and IB were physically associated. In primary MCL tumors, we further demonstrated that the number of cells with IB nuclear retention was linearly correlated with the degree of apoptosis. Our data highlight the role of NF-B pathway in drug response to ibrutinib and selinexor and show the potential of using selinexor to prevent and overcome intrinsic ibrutinib resistance through NF-B inhibition.
2018-07-10 | GSE116810 | GEO
Project description:The use of Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib has achieved a remarkable clinical response in mantle cell lymphoma (MCL). Acquired drug resistance, however, is significant and impacts long-term survival of MCL patients. Here we demonstrate that DNMT3A is involved in ibrutinib resistance. We found that DNMT3A expression is upregulated upon ibrutinib treatment in ibrutinib-resistant MCL cells. Genetic and pharmacological analyses revealed that DNMT3A mediates ibrutinib resistance independent of its DNA-methylation function. Mechanistically, DNMT3A induces the expression of MYC target genes through interaction with the transcription factors MEF2B and MYC, thus mediating metabolic reprogramming to oxidative phosphorylation (OXPHOS). Targeting DNMT3A by a low dose of decitabine inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in a patient-derived xenograft mouse model. These findings suggest that targeting DNMT3A-medited metabolic reprogramming to OXPHOS with decitabine provides a potential therapeutic strategy to overcome ibrutinib resistance in relapsed/refractory MCL.
2024-02-19 | GSE227976 | 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
Project description:Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and NFkB target genes, which undermines the growth and survival of MCL cells. However, BETi treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4, which potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells. BET-PROTACs induce more apoptosis than BETi of MCL cells, including those resistant to ibrutinib. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi, with depletion of c-Myc, CDK4, cyclin D1, and the NFkB transcriptional targets Bcl-xL, XIAP and BTK, while inducing the level of HEXIM1, NOXA and CDKN1A/p21. Treatment with ARV-771, which possesses superior pharmacological properties compared to ARV-825, inhibited the in vivo growth and induced greater survival improvement than the BETi OTX015 of immune-depleted mice engrafted with MCL cells. Co-treatment of ARV-771 with ibrutinib or the BCL2-antagonist venetoclax or CDK4/6 inhibitor palbociclib synergistically induced apoptosis of MCL cells. These studies highlight promising and superior pre-clinical activity of BET-PROTAC than BETi, requiring further in vivo evaluation of BET-PROTAC as a therapy for ibrutinib-sensitive or resistant MCL.
2019-04-26 | GSE98268 | GEO
Project description:We performed a RNA-seq analysis of an ibrutinib-sensitive mantle cell lymphoma cell line treated with ibrutinib for up to 4 d to study transcriptomic adaptations to the BTK inhibitor in surviving cells.
2022-12-22 | GSE214725 | GEO
Project description:In this study we compared the effects of BTK inhibitor on the gene expression, activation of cell signaling pathways, and functional properties of cells derived from a patient with Anaplastic Mantle Cell Lymphoma. we used RNAseq to map the genome-wide gene expression patterns in MCL cells in response to BTK inhibition
2021-02-26 | GSE126726 | GEO
Project description:Mantle Cell lymphoma (MCL) were treated with the BTK inhibitor 1mM CC-292 for 48h We used microarrays to uncover the mechanisms underlying CC-292 activity in Mantle Cell lymphoma (MCL)
2017-09-01 | GSE94328 | GEO