ArrayExpress Uploader04764arrayexpress_sid4The NOTCH1 signaling pathway directly links extracellular signals with transcriptional responses in the cell nucleus and plays a critical...17114293E-GEOD-5827/profile/8773/arrayexpressuploader028cellcell nucleusleukemialymphoblastic leukemiaDec.12, 2014Falsetranscription-profiling-of-human-t-all-cell-culturE-GEOD-5827_A-AFFY-44Transcription profiling of human T-ALL cell cultures treated with Compound E, a gamma-secretase inhibitor or vehicle only (DMSO) for 24 hSep.21, 2014The 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.http://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-5827humanhttp://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-5827/samples/