NR4A1 Inhibition Synergizes with Ibrutinib in Killing Mantle Cell Lymphoma Cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA415591 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6207210.fastq.gz | Fastqsanger.gz | |||
| SRR6207211.fastq.gz | Fastqsanger.gz | |||
| SRR6207212.fastq.gz | Fastqsanger.gz | |||
| SRR6207207.fastq.gz | Fastqsanger.gz | |||
| SRR6207208.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to identify NR4A1 targets by RNA-seq and high-throughput data analysis and verify these genes by quantitative reverse transcription polymerase chain reaction (qRT–PCR) methods. Methods: Jeko/Rec-1 Cas9 control and NR4A1 sgRNA stable cell lines were generated with tet-on system vector, sg RNAs were induced for 48 hours after doxycycline addition, mRNA was extracted and used for RNA sequencing. After TopHat analysis followed by Cufflinks, down/up regulated genes list was generated. qRT–PCR validation was then performed using SYBR Green assays. Results: Using an optimized data analysis workflow and with a fold change ≥1.3 and p value <0.05, thousands of genes were changed. Altered expression of 6 genes was then confirmed with qRT–PCR, demonstrating the high qulity of the RNA-seq method.
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Project description:ibrutinib resistance mantle cell lymphoma
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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.
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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.
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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.
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Project description:Ibrutinib, a bruton's tyrosine kinase inhibitor, was shown to have high response rates in mantle cell lymphoma (MCL), an aggressive B-cell lymphoma. However, emergence of ibrutinib resistance (IR) and subsequent fatal progression is of significant clinical concern. By implementing genomics, chemical proteomics and drug screening, we report that enhancer remodeling-mediated transcriptional activation and adaptive signaling changes drive the malignant phenotype of IR. Accordingly, IR MCL cells are vulnerable to inhibition of the transcriptional machinery and especially to inhibition of cyclin-dependent kinase 9 (CDK9). Thus, targeting transcriptional activation offers a novel strategy to prevent the emergence of IR and overcome IR via impeding IR-associated cellular signaling reprogramming in MCL. In addition, our ex-vivo microfluidic image-based functional drug screen can function not only as new technology platforms for predicting clinical therapeutic response but also, in conjunction with genomic profiling in primary MCL samples, identify the molecular vulnerabilities for drug resistance evolution, providing insight into the underlying IR mechanisms for MCL and other B-cell malignancies
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Project description:Ibrutinib, a bruton's tyrosine kinase inhibitor, was shown to have high response rates in mantle cell lymphoma (MCL), an aggressive B-cell lymphoma. However, emergence of ibrutinib resistance (IR) and subsequent fatal progression is of significant clinical concern. By implementing genomics, chemical proteomics and drug screening, we report that enhancer remodeling-mediated transcriptional activation and adaptive signaling changes drive the malignant phenotype of IR. Accordingly, IR MCL cells are vulnerable to inhibition of the transcriptional machinery and especially to inhibition of cyclin-dependent kinase 9 (CDK9). Thus, targeting transcriptional activation offers a novel strategy to prevent the emergence of IR and overcome IR via impeding IR-associated cellular signaling reprogramming in MCL. In addition, our ex-vivo microfluidic image-based functional drug screen can function not only as new technology platforms for predicting clinical therapeutic response but also, in conjunction with genomic profiling in primary MCL samples, identify the molecular vulnerabilities for drug resistance evolution, providing insight into the underlying IR mechanisms for MCL and other B-cell malignancies
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