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| Status |
Public on Nov 13, 2006 |
| Title |
NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
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
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| 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.
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| Contributor(s) |
Palomero T, Lim W, Odom D, Sulis M, Real PJ, Margolin A, Barnes KC, O'Neil J, Neuberg D, Weng A, Aster J, Sigaux F, Soulier J, Look T, Young R, Califano A, Ferrando AA |
| Citation(s) |
17114293, 28174276 |
| Submission date |
Sep 13, 2006 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Adolfo A Ferrando |
| E-mail(s) |
af2196@columbia.edu
|
| Phone |
212-851-4611
|
| Organization name |
Columbia University
|
| Department |
Institute for Cancer Genetics
|
| Street address |
1130 St Nicholas Ave Irving Cancer Research Center 5-505A
|
| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10032 |
| Country |
USA |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (28)
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| Relations |
| BioProject |
PRJNA97217 |
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