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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Lymphomas that recur after MYC suppression continue to exhibit oncogene addiction

ABSTRACT: The suppression of oncogenic levels of MYC is sufficient to induce sustained tumor regression associated with proliferative arrest, differentiation, cellular senescence and/or apoptosis, a phenomenon known as oncogene addiction. However, after prolonged inactivation of MYC in a conditional transgenic mouse model of Em-tTA/tetO-MYC T-acute lymphomablastic lymphoma (T-ALL), some of the tumors recur, recapitulating what is frequently observed in human tumors in response to targeted therapies. Here we report that these recurring lymphomas express high levels of either transgenic or endogenous Myc suggesting that tumors continue to be addicted to oncogenic levels of MYC. Many of the recurring lymphomas (76%) harbored mutations in the tetracycline transactivator (tTA) resulting in expression of the MYC transgene even in the presence of doxycycline. Many of the remaining recurring tumors expressed high levels of endogenous Myc which was in some cases associated with a genomic rearrangement of the endogenous Myc locus or overexpression of Notch1. Gene expression profiling confirmed that the primary and recurring tumors have highly similar transcriptomes. Importantly, shRNA-mediated suppression of the high levels of MYC in recurring tumors elicited both suppression of proliferation and increased apoptosis confirming that these tumors remain oncogene addicted. These results suggest that tumors caused by MYC overexpression remain addicted to high levels of expression of this oncogene. 13 samples, no replicates included

ORGANISM(S): Mus musculus

SUBMITTER: Andrew Gentles

PROVIDER: E-GEOD-32341 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Lymphomas that recur after MYC suppression continue to exhibit oncogene addiction

Project description:The suppression of oncogenic levels of MYC is sufficient to induce sustained tumor regression associated with proliferative arrest, differentiation, cellular senescence and/or apoptosis, a phenomenon known as oncogene addiction. However, after prolonged inactivation of MYC in a conditional transgenic mouse model of Em-tTA/tetO-MYC T-acute lymphomablastic lymphoma (T-ALL), some of the tumors recur, recapitulating what is frequently observed in human tumors in response to targeted therapies. Here we report that these recurring lymphomas express high levels of either transgenic or endogenous Myc suggesting that tumors continue to be addicted to oncogenic levels of MYC. Many of the recurring lymphomas (76%) harbored mutations in the tetracycline transactivator (tTA) resulting in expression of the MYC transgene even in the presence of doxycycline. Many of the remaining recurring tumors expressed high levels of endogenous Myc which was in some cases associated with a genomic rearrangement of the endogenous Myc locus or overexpression of Notch1. Gene expression profiling confirmed that the primary and recurring tumors have highly similar transcriptomes. Importantly, shRNA-mediated suppression of the high levels of MYC in recurring tumors elicited both suppression of proliferation and increased apoptosis confirming that these tumors remain oncogene addicted. These results suggest that tumors caused by MYC overexpression remain addicted to high levels of expression of this oncogene.

2011-09-24 | GSE32341 | GEO

Gene Expression Analysis of Transgenic Myc-Driven Liver Tumor Formation and Regression

Project description:Gene expression changes were examined in transgenic MYC-driven liver cancers at different time points as tumors formed and upon early regression. Time points evaluated include: Control (non-tumor bearing), Pre-tumor (mice were removed from doxyclycine in their diet to induce MYC oncogene expression for 4-5 weeks), Tumor (tumor nodules from mice that had been off of doxycycline for 8-9 weeks) and Early tumor regression (tumor-bearing mice were placed back on doxycycline for 72 hrs to inhibit MYC oncogene expresion). MYC-Driven Mouse Tumor Models are described in Schahaf, et al., Nature, 2004 and Goga, et al., Nature Medicine, 2007. 11 Total Samples: 3 Control, 4 Pre-Tumor, 4 Tumor, 4 Early Tumor Regression. Control = LAP-tTA transgenic mice. Others = TRE-MYC x LAP-tTA double transgenic mice (doxy off).

2011-07-06 | E-GEOD-28198 | biostudies-arrayexpress

Myc-dependent gene activation and repression in oncogene-addicted liver tumors

Project description:Myc-dependent gene activation and repression in oncogene-addicted liver tumors

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MYC-driven mouse HCC proteomics

Project description:To identify proteomic signatures associated with hepatocellular carcinoma driven by MYC overexpression, proteomics was performed on the LAP-tTA/tetO-MYC mouse conditional liver cancer model. Upon MYC activation, mice form liver cancer. Differential proteomics was performed in "MYC on" (MYC-HCC) mouse liver tumors versus mouse control normal liver tissue (where MYC was not overexpressed to drive tumorigenesis -- "MYC off").

2022-10-12 | PXD031478 | Pride

Gene Expression Differences in MYC and RAS Driven Liver Cancer Transgenic

Project description:MYC and RAS signaling are two oncogene pathways important in human liver cancer. We sought to model liver cancer driven by either MYC or RAS using conditional LAP-tTA crossed to either TRE-MYC or TRE-HRAS models in the FVB/N background, and to understand oncogenic signaling pathways that are distinct between each model. Non-tumor tissue, from LAP-tTTA (LT2) mice were used as controls. In this study, we generated tumors from either MYC or RAS driven tumors and compared global gene expression changes to each other and control samples.

2018-09-20 | GSE73295 | GEO

Mus musculus

Project description:Myc-dependent gene activation and repression in oncogene-addicted liver tumors (RNA-seq)

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Project description:Myc-dependent gene activation and repression in oncogene-addicted liver tumors (ChIP-seq)

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MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies

Project description:We delineate the immunobiology during MYC oncogene-driven lymphomagenesis by RNA sequencing analysis followed by CIBERSORT of bulk splenic samples from healthy and SRa-tTA/tet-O-MYC mice before and after MYC inactivation. The data set also delineates global changes in signaling molecules in healthy spleens (controls) and lymphomagenic spleens in MYC ON and MYC OFF states.

2020-04-20 | GSE106078 | GEO

MYC threshold required to maintain tumor phenotype

Project description:We demonstrate that there is a level of MYC expression that is required for maintaining a tumor phenotype and at this threshold there is a switch from a state of cellular proliferation to a state of proliferative arrest and apoptosis. We analyzed changes in gene expression by oligonucleotide microarray analysis and quantitative PCR and found significant changes (FDR=5%) in 2348 down regulated genes and 1573 upregulated genes. Critical changes in gene expression that occurred at or near the threshold level of MYC expression includes genes that have been implicated in G1/S, G2/M cell cycle checkpoint pathways and death receptor/apoptosis signaling. Keywords: Dose response - MYC inactivation by doxycycline treatment 11 samples, replicates not included

2010-05-25 | E-GEOD-10200 | biostudies-arrayexpress

The 3’-UTR of MYC couples RNA polymerase II function to ribonucleotide levels

Project description:Deregulated expression of MYC enhances glutamine utilization and renders cell survival dependent on glutamine, inducing “glutamine addiction”. Surprisingly, colon cancer cells that express high levels of MYC due to WNT pathway mutations, are not glutamine-addicted but undergo a reversible cell cycle arrest upon glutamine deprivation. We show here that glutamine deprivation suppresses translation of endogenous MYC via the 3’-UTR of the MYC mRNA, enabling escape from apoptosis. This regulation is mediated by glutamine-dependent changes in adenosine nucleotide levels. Glutamine deprivation causes a global reduction in promoter association of RNA Polymerase II (RNAPII) and slows transcriptional elongation. While activation of MYC restores binding of MYC and RNAPII function on most promoters, restoration of elongation is imperfect and activation of MYC in the absence of glutamine causes stalling of RNAPII on multiple genes, correlating with R-loop formation. Stalling of RNAPII and R-loop formation can cause DNA damage, arguing that the MYC 3’-UTR is critical for maintaining genome stability when ribonucleotide levels are low.

2022-02-28 | PXD005829 | Pride

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