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Total gene expression analysis of LMP2A/λ-MYC and λ-MYC tumors

ABSTRACT: We have developed a transgenic mouse model for Epstein-Barr virus-associated Burkitt's lymphoma. Transgenic mice that express LMP2A and MYC in B cells develop spontaneous lymph node tumors at different rates. Tumor onset occurs at approximately 40-60 days in LMP2A/λ-MYC mice and at 100-200 days in λ-MYC mice. This study compared total gene expression in the tumor cells from each genotype, as well as in B cells isolated from 3 week old mice prior to tumor onset. Comparison of total gene expression in tumor cells from LMP2A/λ-MYC and λ-MYC transgenic mice identified a short list of differentially expressed genes. Comparison of gene expression in B cells from the spleens of 3 week old mice, in contrast, identified a 10-fold increase in the number of differentially expressed genes. B cells from the spleens of 3 week old LMP2A/λ-MYC (n=5), λ-MYC (n=5), LMP2A (n=3), and WT (n=3) transgenic mice were purified using magnetic-activated cell sorting (MACS) beads purchased from Miltenyi for CD19 positive selection. Total RNA was isolated from these purified B cells, as well as from cervical lymph node tumor cells that developed in LMP2A/λ-MYC (n=7) and λ-MYC (n=5) transgenic mice using RNeasy RNA extraction kit from QIAGEN. Cervical lymph node tumor cells were >90% positive for the B cell marker B220, and were not further purified. Total gene expression was assessed in each sample, along with heart and brain reference samples using MouseRef-8 v2.0 Expression Bead Chips purchased from Illumina. GeneSpring analysis software was used to analyze the expression data and identify significantly differentially expressed genes (fold change >1.5-fold and false discovery rate< 0.05).

ORGANISM(S): Mus musculus

SUBMITTER: Kathryn Bieging

PROVIDER: E-GEOD-26918 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Total gene expression analysis of LMP2A/λ-MYC and λ-MYC tumors

Project description:We have developed a transgenic mouse model for Epstein-Barr virus-associated Burkitt's lymphoma. Transgenic mice that express LMP2A and MYC in B cells develop spontaneous lymph node tumors at different rates. Tumor onset occurs at approximately 40-60 days in LMP2A/λ-MYC mice and at 100-200 days in λ-MYC mice. This study compared total gene expression in the tumor cells from each genotype, as well as in B cells isolated from 3 week old mice prior to tumor onset. Comparison of total gene expression in tumor cells from LMP2A/λ-MYC and λ-MYC transgenic mice identified a short list of differentially expressed genes. Comparison of gene expression in B cells from the spleens of 3 week old mice, in contrast, identified a 10-fold increase in the number of differentially expressed genes.

2011-10-26 | GSE26918 | GEO

Interferon lambda restricts West Nile virus neuroinvasion by enhancing integrity of the blood-brain barrier

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Interferon lambda restricts West Nile virus neuroinvasion by enhancing integrity of the blood-brain barrier

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Project description:Total gene expression analysis of LMP2A/λ-MYC and λ-MYC tumors

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Project description:Epstein-Barr virus (EBV) infects human B cells and reprograms them to allow virus replication and persistence. One key viral factor in this process is latent membrane protein 2A (LMP2A), which has been described as a B cell receptor (BCR) mimic promoting malignant transformation. However, how LMP2A signaling contributes to tumorigenesis remains elusive. By systematically comparing LMP2A and BCR signaling using quantitative phosphoproteomics and transcriptome profiling, we identified molecular mechanisms through which LMP2A affects B cell biology. Consistent with previous literature, we found that LMP2A mimics a subset of BCR signaling events, including tyrosine-phosphorylation of the kinase SYK, the calcium initiation complex consisting of BLNK, BTK, PLC2, and its downstream transcription factor NFAT. However, the vast majority of LMP2A-induced signaling events markedly differed from those induced by BCR stimulation. These included differential phosphorylation of kinases, phosphatases, adaptor proteins, transcription factors such as NFB and TCF3, as well as widespread changes in the transcriptional output of LMP2A-expressing B cells. LMP2A affected apoptosis and cell cycle checkpoints by dysregulating the expression of apoptosis regulators such as Bcl-xL and the tumor suppressor retinoblastoma-associated protein (RB1). Accordingly, LMP2A cooperated with drivers of Burkitt lymphoma, overexpressed MYC and an oncogenic cyclin D3 mutant, by counteracting the pro-apoptotic effects of MYC and by further inhibiting RB1 function to promote cell growth. Our results indicate that LMP2A rewires rather than mimics BCR signaling, promoting a signaling output that predisposes EBV-infected B cells to hyperproliferation and eventual malignant transformation.

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