Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA202901 | ENA |
REPOSITORIES: ENA
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Project description:Immuno-chemotherapy regimens elicit high response rates in B-cell non-Hodgkin lymphoma but heterogeneity in response duration is observed, with some patients achieving cure and others showing refractory disease or relapse. Using a transcriptome-powered targeted proteomics screen, we discovered a gene regulatory circuit involving the nuclear factor CYCLON which characterizes aggressive disease and resistance to the anti-CD20 monoclonal antibody, Rituximab, in high-risk B-cell lymphoma. CYCLON knockdown was found to inhibit the aggressivity of MYC-overexpressing tumors in mice and to modulate gene expression programs of biological relevance to lymphoma. Furthermore, CYCLON knockdown increased the sensitivity of human lymphoma B cells to Rituximab in vitro and in vivo. Strikingly, this effect could be mimicked by in vitro treatment of lymphoma B cells with a small molecule inhibitor for BET bromodomain proteins (JQ1). In summary, this work has identified CYCLON as a new MYC cooperating factor that drives aggressive tumor growth and Rituximab resistance in lymphoma. This resistance mechanism is amenable to next-generation epigenetic therapy by BET bromodomain inhibition, thereby providing a new combination therapy rationale for high-risk lymphoma. We have identified CYCLON has a nuclear factor involved in tumor progression and treatment resistance in aggressive lymphoma. In order to get further insights into the molecular mechanisms related to the expression of this factor, we used Raji cells to compared gene expression profiles of control and CYCLON knock-down cell lines. Stable cell lines have been established using lentiviral transduction of Raji Burkitt lymphoma B cells with either a control (non-targeting) shRNA sequence or CYCLON shRNA constructs under puromycin selection. Non-transduced cells were also analyzed as a control. 4 replicates were analyzed for each conditions.
2013-06-01 | E-GEOD-46873 | biostudies-arrayexpress
Project description:Immuno-chemotherapy regimens elicit high response rates in B-cell non-Hodgkin lymphoma but heterogeneity in response duration is observed, with some patients achieving cure and others showing refractory disease or relapse. Using a transcriptome-powered targeted proteomics screen, we discovered a gene regulatory circuit involving the nuclear factor CYCLON which characterizes aggressive disease and resistance to the anti-CD20 monoclonal antibody, Rituximab, in high-risk B-cell lymphoma. CYCLON knockdown was found to inhibit the aggressivity of MYC-overexpressing tumors in mice and to modulate gene expression programs of biological relevance to lymphoma. Furthermore, CYCLON knockdown increased the sensitivity of human lymphoma B cells to Rituximab in vitro and in vivo. Strikingly, this effect could be mimicked by in vitro treatment of lymphoma B cells with a small molecule inhibitor for BET bromodomain proteins (JQ1). In summary, this work has identified CYCLON as a new MYC cooperating factor that drives aggressive tumor growth and Rituximab resistance in lymphoma. This resistance mechanism is amenable to next-generation epigenetic therapy by BET bromodomain inhibition, thereby providing a new combination therapy rationale for high-risk lymphoma. We have identified CYCLON has a nuclear factor involved in tumor progression and treatment resistance in aggressive lymphoma. In order to get further insights into the molecular mechanisms related to the expression of this factor, we used Raji cells to compared gene expression profiles of control and CYCLON knock-down cell lines.
2013-06-01 | GSE46873 | GEO
Project description:The MYC transcription factor is a master regulator of diverse cancer pathways and somatic cell reprogramming. MYC is a compelling therapeutic target that exhibits cancer-specific cellular effects. Pharmacologic inhibition of MYC function has proven challenging due to its numerous modes of forced expression and the difficulty of disrupting protein-DNA interactions. Here we demonstrate the rapid and potent abrogation of MYC gene transcription by representative small molecule bromodomain inhibitors of the BET family of chromatin adaptors. This transcriptional suppression of MYC was observed in the context of the natural, chromosomally translocated, and amplified gene locus. Inhibition of BET bromodomain-promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G1 arrest and extensive apoptosis in a variety of leukemia and lymphoma cell lines. Exogenous expression of MYC from an artificial promoter that is resistant to BET regulation significantly protected cells from growth suppression by BET inhibitors and revealed that MYC exerts a direct and tight control of key pro-growth and anti-apoptotic target genes. Transcriptional profiling of two cells after 4 and 8 hours of treatment with BET inhibitor shows that both MYC and its targets are strongly down-regulated. We thus demonstrate that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains, and suggest that such inhibitors may have broad clinical applicability given the widespread pathogenetic role of MYC in cancer. LP-1, a multiple myeloma cell line, and Raji, a Burkitt lymphoma cell line, were treated with BET inhibitor and an inactive enantiomer for 4 or 8 hours. Two biological replicates of each sample were profiled on exon arrays.
2011-09-18 | E-GEOD-29449 | biostudies-arrayexpress
Project description:The MYC transcription factor is a master regulator of diverse cancer pathways and somatic cell reprogramming. MYC is a compelling therapeutic target that exhibits cancer-specific cellular effects. Pharmacologic inhibition of MYC function has proven challenging due to its numerous modes of forced expression and the difficulty of disrupting protein-DNA interactions. Here we demonstrate the rapid and potent abrogation of MYC gene transcription by representative small molecule bromodomain inhibitors of the BET family of chromatin adaptors. This transcriptional suppression of MYC was observed in the context of the natural, chromosomally translocated, and amplified gene locus. Inhibition of BET bromodomain-promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G1 arrest and extensive apoptosis in a variety of leukemia and lymphoma cell lines. Exogenous expression of MYC from an artificial promoter that is resistant to BET regulation significantly protected cells from growth suppression by BET inhibitors and revealed that MYC exerts a direct and tight control of key pro-growth and anti-apoptotic target genes. Transcriptional profiling of two cells after 4 and 8 hours of treatment with BET inhibitor shows that both MYC and its targets are strongly down-regulated. We thus demonstrate that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains, and suggest that such inhibitors may have broad clinical applicability given the widespread pathogenetic role of MYC in cancer.
2011-09-19 | GSE29449 | GEO
Project description:MYC genes are frequently amplified and correlate with poor prognosis in MB. BET bromodomains recognize acetylated lysine residues and often promote and maintain MYC transcription. Certain cyclin-dependent kinases (CDKs) are further known to support MYC stabilization in tumor cells. In this report, MB cells were suppressed by combined targeting of MYC expression and MYC stabilization using BET bromodomain inhibition and CDK2 inhibition, respectively. Such combination treatment worked synergistically and caused cell cycle arrest as well as massive apoptosis. Immediate transcriptional changes from this combined MYC blockade were found using RNA-Seq profiling and showed remarkable similarities to changes in MYC target gene expression when MYCN was turned off with doxycycline in our MYCN-inducible animal model for Group 3 MB. In addition, the combination treatment significantly prolonged survival as compared to single agent therapy in orthotopically transplanted human Group 3 MB with MYC amplifications. Our data suggests that dual inhibition of CDK2 and BET bromodomains can be a novel treatment approach for suppressing MYC-driven cancer.
2018-06-06 | GSE107405 | GEO
Project description:MYC-amplified medulloblastomas are highly lethal tumors. BET bromodomain inhibition was recently described to downregulate MYC-associated transcriptional activity in various cancer subtypes. To investigate whether JQ1, a BET bromodomain inhibitor is downregulation MYC and MYC-associated transcriptional activity, we performed global gene expression profiling of five medulloblastomas MYC-amplified patient-derived cell lines treated by JQ1 and the inactive form of JQ1. Five medulloblastomas patient-derived MYC-amplified cell lines were treated with the active and the inactive form of the drug (JQ1S or JQ1R, respectively, 1μM for 24 hours) followed by RNA extraction and hybridization on Affymetrix microarrays
2013-12-02 | E-GEOD-51020 | biostudies-arrayexpress
Project description:MYC-amplified medulloblastomas are highly lethal tumors. BET bromodomain inhibition was recently described to downregulate MYC-associated transcriptional activity in various cancer subtypes. To investigate whether JQ1, a BET bromodomain inhibitor is downregulation MYC and MYC-associated transcriptional activity, we performed global gene expression profiling of five medulloblastomas MYC-amplified patient-derived cell lines treated by JQ1 and the inactive form of JQ1.
2013-12-02 | GSE51020 | GEO
Project description:BET bromodomain inhibitors are known to block prostate cancer cell survival through suppression of c-Myc and androgen receptor (AR) function. However, little is known about other transcriptional modulators whose function is blocked by these drugs and the anti-tumor activity of BET bromodomain inhibition in AR-independent castration-resistant prostate cancers (CRPC), whose frequency may be increasing. In this study we determined that BET bromodomain inhibition suppresses survival of a diverse set of CRPC cell models, including those that do not express the AR or in which c-Myc is not suppressed. To identify additional transcriptional regulators whose suppression contributes to the anti-tumor effects of BET bromodomain inhibition, we treated multiple CRPC cell lines with the BET bromodomain inhibitor JQ1, measured genome-wide gene expression changes, and then used the Master Regulator Inference Algorithm (MARINa). This approach identified transcriptional regulators whose function is blocked by JQ1 and whose suppression recapitulates the effects of BET bromodomain inhibition. High Expression of these Master Regulators in aggressive human CRPC demonstrates their clinical relevance.
2019-03-20 | GSE98069 | GEO
Project description:Targeting BET bromodomain proteins utilizing small molecules in an emerging anti-cancer strategy with clinical evaluation of at least six inhibitors now underway. While MYC downregulation was initially proposed as a key mechanistic property of BET inhibitors, recent evidence suggests that additional anti-tumor activities are important. Using the Eμ-Myc model of B-cell lymphoma we demonstrate that BET inhibition with JQ1 is a potent inducer of p53-independent apoptosis that occurs in the absence of effects on Myc gene expression. JQ1 skews the expression of pro-apoptotic (Bim) and anti-apoptotic (BCL-2/BCL-xL) BCL-2 family members to directly engage the mitochondrial apoptotic pathway. Consistent with this, Bim knockout or Bcl-2 overexpression inhibited apoptosis induction by JQ1. We identified lymphomas that were either intrinsically resistant to JQ1-mediated death or acquired resistance following in vivo exposure. Strikingly, in both instances BCL-2 was strongly upregulated and was concomitant with activation of RAS pathways. Eμ-Myc lymphomas engineered to express activated Nras upregulated BCL-2 and acquired a JQ1-resistance phenotype. These studies provide important information on mechanisms apoptosis induction and resistance to BET-inhibition, while providing further rationale for the translation of BET inhibitors in aggressive B-cell lymphomas.
2016-09-18 | GSE87050 | GEO