PRPS activity governs redox homeostasis in MYC-driven lymphoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1188578 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31414621_1.fastq.gz | Fastqsanger.gz | |||
| SRR31414621_2.fastq.gz | Fastqsanger.gz | |||
| SRR31414622_1.fastq.gz | Fastqsanger.gz | |||
| SRR31414622_2.fastq.gz | Fastqsanger.gz | |||
| SRR31414623_1.fastq.gz | Fastqsanger.gz |
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Project description:Myc hyperactivation coordinately regulates numerous metabolic processes to drive lymphomagenesis. However, the temporal and epistatic relationships between the medley of pathways, factors, and mechanisms that must functionally cooperate to preserve homeostasis in Myc-overexpressing cells remain largely unknown. Here, we characterize the earliest metabolic alterations upon induction of oncogenic Myc and pinpoint the major determinants of redox balance in Myc-overexpressing lymphomas. We find that Myc rapidly stimulates the oxidative pentose phosphate pathway (oxPPP), nucleic acid synthesis, and mitochondrial respiration, which collectively steers cellular equilibrium to a more oxidative state. Acting at the nexus of these processes, we identify Myc-dependent hyperactivation of the phosphoribosyl pyrophosphate synthetase (PRPS) enzyme as the primary regulator of redox status in lymphoma cells. Mechanistically, Myc induces expression of the allosteric feedback refractory PRPS2 isozyme, thereby remodeling the PRPS enzyme complex to a more active state that efficiently funnels ribose-5-phosphate from the PPP to downstream nucleotides. Genetic inactivation of PRPS2 increases oxPPP flux and futile cycling, leading to increased NADPH levels and reductive stress-mediated cell death. Employing a pharmacological screen in wild-type, PRPS1- or PRPS2-knockout lymphoma cells to reveal cooperative functional interactions, we discovered that cells engineered to lack PRPS1 or PRPS2 displayed opposing differential sensitivities to compounds targeting the glutathione and thioredoxin systems, outlining effective rational combinatorial therapeutic approaches in Myc-driven lymphomas. Collectively, our work unravels how the activity of one critical node amongst the expansive metabolic architecture of a cell can be tuned by an oncogenic pathway to alter redox homeostasis and create new exploitable dependencies
2025-02-20 | GSE282435 | GEO
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Project description:Myc hyperactivation coordinately regulates numerous metabolic processes to drive lymphomagenesis. Here, we elucidate the temporal and functional relationships between the medley of pathways, factors, and mechanisms that cooperate to control redox homeostasis in Myc-overexpressing B cell lymphomas. We find that Myc overexpression rapidly stimulates the oxidative pentose phosphate pathway (oxPPP), nucleotide synthesis, and mitochondrial respiration, which collectively steers cellular equilibrium to a more oxidative state. We identify Myc-dependent hyperactivation of the phosphoribosyl pyrophosphate synthetase (PRPS) enzyme as a primary regulator of redox status in lymphoma cells. Mechanistically, we show that genetic inactivation of the PRPS2 isozyme, but not PRPS1, in MYC-driven lymphoma cells leads to elevated NADPH levels and reductive stress-mediated death. Employing a pharmacological screen, we demonstrate how targeting PRPS1 or PRPS2 elicits opposing sensitivity or resistance, respectively, to chemotherapeutic agents affecting the thioredoxin and glutathione network, thus providing a therapeutic blueprint for treating MYC-driven lymphomas.
| S-EPMC11761749 | biostudies-literature
Project description:miRNA expression profiling of murine MYC-dependent lymphoma cell lines harboring the MYC-transgene in a Tet-off system comparing control untreated lymphoma cells (high MYC expression state) with 18hours Dox treated lymphoma cells (low MYC expression state). Keywords: inducible expression system
2008-08-12 | GSE12394 | GEO
Project description:Identification of miRNA differentially expressed between MYC-translocation positive and and MYC-translocation negative Burkitt Lymphoma and their impact on gene expression profile Study of microRNA profile of MYC-translocation positive and MYC-translocation negative Burkitt Lymphoma cases in order to uncover possible differences at the molecular level
2015-08-05 | E-GEOD-71471 | biostudies-arrayexpress
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Project description:miRNA expression profiling of murine MYC-dependent lymphoma cell lines harboring the MYC-transgene in a Tet-off system comparing control untreated lymphoma cells (high MYC expression state) with 18hours Dox treated lymphoma cells (low MYC expression state). Keywords: inducible expression system Two-condition experiment, Dox vs. NoDox treatment. Biological replicates: 26 distinct cell lines, 1 technical replicate. Four replicates per array.
2010-05-25 | E-GEOD-12394 | biostudies-arrayexpress
Project description:Background: MYC is a transcription factor encoded by the c-MYC gene (thereafter termed MYC). MYC is key transcription factor involved in many central cellular processes including ribosomal biogenesis. MYC is overexpressed in the majority of human tumours including aggressive B-cell lymphoma especially Burkitt's lymphoma. Although Burkitt's lymphoma is a highlight example for MYC overexpression due to a chromosomal translocation, no global analysis of MYC binding sites by chromatin immunoprecipitation (ChIP) followed by global next generation sequencing (ChIP-Seq) has been conducted so far in Burkitt's lymphoma. Methodology/Principal Findings: ChIP-Seq was performed with a MYC-specific antibody giving rise to 7,054 predicted MYC binding sites after bioinformatics analysis of a total of 19 million sequence reads. In line with previous findings, binding sites accumulate in gene sets known to be involved in the ribosomal biogenesis, histone acetyltransferase and methyltransferase complexes and the cell cycle demonstrating a regulatory role of MYC in these processes. Unexpectedly, MYC binding sites also accumulate in genes typically expressed in mature B-cells. To assess the functional consequences of altered MYC binding, the ChIP-Seq data were supplemented with siRNA mediated knock-downs of MYC in BL cell lines followed by gene expression profiling. Interestingly, amongst others, genes involved in B-cell function were up-regulated in response to MYC silencing. Conclusion/Significance: The 7,054 MYC-binding sites identified by our ChIP-Seq approach greatly extend the knowledge regarding MYC binding in Burkitt's lymphoma and sheds further light on the enormous complexity of the MYC regulatory network. Especially our observation that (i) many B-cell relevant genes are targeted by MYC and (ii) that MYC down-regulation leads to an up-regulation of B-cell genes highlights an interesting aspect of BurkittM-BM-4s lymphoma biology. [ChIP-Seq] Analysis of MYC DNA binding sites by ChiP-Seq in 5 BurkittM-BM-4s lymphoma cell lines (Raji, Ramos, Blue1, BL41, CA46) [mRNA expression profiling] siRNA-mediated knock-down of MYC was done employing the BL cell lines Raji, BL41 and Blue1 in order to detect MYC-driven gene expression changes. For this purpose, the cells were Amaxa-transfected using MYC smart pool siRNA and control siRNA (Thermo Scientific/Dharmacon, Erembodegem, Belgium), respectively.
2011-11-28 | E-GEOD-30726 | biostudies-arrayexpress
Project description:Identification of miRNA differentially expressed between MYC-translocation positive and and MYC-translocation negative Burkitt Lymphoma and their impact on gene expression profile
2015-08-05 | GSE71471 | GEO
Project description:Background: MYC is a transcription factor encoded by the c-MYC gene (thereafter termed MYC). MYC is key transcription factor involved in many central cellular processes including ribosomal biogenesis. MYC is overexpressed in the majority of human tumours including aggressive B-cell lymphoma especially Burkitt's lymphoma. Although Burkitt's lymphoma is a highlight example for MYC overexpression due to a chromosomal translocation, no global analysis of MYC binding sites by chromatin immunoprecipitation (ChIP) followed by global next generation sequencing (ChIP-Seq) has been conducted so far in Burkitt's lymphoma. Methodology/Principal Findings: ChIP-Seq was performed with a MYC-specific antibody giving rise to 7,054 predicted MYC binding sites after bioinformatics analysis of a total of 19 million sequence reads. In line with previous findings, binding sites accumulate in gene sets known to be involved in the ribosomal biogenesis, histone acetyltransferase and methyltransferase complexes and the cell cycle demonstrating a regulatory role of MYC in these processes. Unexpectedly, MYC binding sites also accumulate in genes typically expressed in mature B-cells. To assess the functional consequences of altered MYC binding, the ChIP-Seq data were supplemented with siRNA mediated knock-downs of MYC in BL cell lines followed by gene expression profiling. Interestingly, amongst others, genes involved in B-cell function were up-regulated in response to MYC silencing. Conclusion/Significance: The 7,054 MYC-binding sites identified by our ChIP-Seq approach greatly extend the knowledge regarding MYC binding in Burkitt's lymphoma and sheds further light on the enormous complexity of the MYC regulatory network. Especially our observation that (i) many B-cell relevant genes are targeted by MYC and (ii) that MYC down-regulation leads to an up-regulation of B-cell genes highlights an interesting aspect of Burkitt´s lymphoma biology.
2011-11-28 | GSE30726 | GEO