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NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth

ABSTRACT: The NOTCH1 signaling pathway directly links extracellular signals with transcriptional responses in the cell nucleus and plays a critical role during T-cell development and in the pathogenesis over 50% of human T-cell lymphoblastic leukemia (T-ALL) cases. However, little is known about the transcriptional programs activated by NOTCH1. Using an integrative systems biology approach we show that NOTCH1 controls a feed-forward loop transcriptional network that promotes cell growth. Inhibition of NOTCH1 signaling in T-ALL cells led to a reduction in cell size and elicited a gene expression signature dominated by downregulated biosynthetic pathway genes. By integrating gene expression array and ChIP-on-chip data, we show that NOTCH1 directly activates multiple biosynthetic routes and induces c-MYC gene expression. Reverse engineering of regulatory networks from expression profiles showed that NOTCH1 and c-MYC govern two directly interconnected transcriptional programs containing common target genes that together regulate the growth of primary T-ALL cells. These results identify c-MYC as an essential mediator of NOTCH1 signaling and integrate NOTCH1 activation with oncogenic signaling pathways upstream of c-MYC. Keywords: Drug treatment

ORGANISM(S): Homo sapiens

PROVIDER: GSE5827 | GEO | 2006/11/13

SECONDARY ACCESSION(S): PRJNA97217

REPOSITORIES: GEO

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Transcription profiling of human T-ALL cell cultures treated with Compound E, a gamma-secretase inhibitor or vehicle only (DMSO) for 24 h

Project description:The NOTCH1 signaling pathway directly links extracellular signals with transcriptional responses in the cell nucleus and plays a critical role during T-cell development and in the pathogenesis over 50% of human T-cell lymphoblastic leukemia (T-ALL) cases. However, little is known about the transcriptional programs activated by NOTCH1. Using an integrative systems biology approach we show that NOTCH1 controls a feed-forward loop transcriptional network that promotes cell growth. Inhibition of NOTCH1 signaling in T-ALL cells led to a reduction in cell size and elicited a gene expression signature dominated by downregulated biosynthetic pathway genes. By integrating gene expression array and ChIP-on-chip data, we show that NOTCH1 directly activates multiple biosynthetic routes and induces c-MYC gene expression. Reverse engineering of regulatory networks from expression profiles showed that NOTCH1 and c-MYC govern two directly interconnected transcriptional programs containing common target genes that together regulate the growth of primary T-ALL cells. These results identify c-MYC as an essential mediator of NOTCH1 signaling and integrate NOTCH1 activation with oncogenic signaling pathways upstream of c-MYC. Experiment Overall Design: Duplicated cultures of T-ALL cell lines were treated with Compound E, a gamma-secretase inhibitor or vehicle only (DMSO) for 24 h and analyzed using oligonucleotide microarrays. Gene expression changes were analyzed in the context of loss of NOTCH1 signaling induced by the gamma secretase inhibitor treatment.

2008-06-14 | E-GEOD-5827 | biostudies-arrayexpress

Transcription profiling of human T-ALL cell lines with NOTCH1 activating mutations following CompE treatment

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Homo sapiens

Project description:NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth

| PRJNA97217 | ENA

A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma.

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Project description:T cell clonal expansion and differentiation are critically dependent on the transcription factor c-Myc (Myc). Herein we use quantitative mass-spectrometry to reveal how Myc controls antigen receptor driven cell growth and proteome restructuring in CD4+ and CD8+ T cells. Quantitative proteomics was performed on naive wild-type (WT) and 24 hr T cell receptor (TCR) activated Myc WT and Myc-deficient T cells. Analysis of copy numbers per cell of >7000 proteins provides new understanding of the selective role of Myc in controlling the protein machinery that shapes T cell fate. The data identify both Myc dependent and independent metabolic processes in immune activated T cells. We uncover that a primary function of Myc is to induce amino acid transporter expression. Quantitative proteomics of 24 hr TCR activated Slc7a5 WT and Slc7a5-deficient CD4 T cells reveals that loss of a single Myc-controlled amino transporter, Slc7a5, can effectively phenocopy the impact of Myc deletion. This study thus provides a comprehensive map of how Myc selectively shapes T cell phenotypes and reveals that Myc induction of amino acid transport is pivotal for subsequent bioenergetic and biosynthetic programs.

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