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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

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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

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Project description:Oncogenes NOTCH1 and MYC directly regulate HSF1 and other critical proteins of the stress-response pathway in T-ALL. This GRO-Seq experiment demonstrates that release from NOTCH1 inhibition results in upregulation of HSF1 and other key HSPs.

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