title: 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 down-regulated 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.
authors.affiliation: Institute for Cancer Genetics and Joint Centers for Systems Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Palomero
authors.forename: Wei Keat
authors.initials: WK
authors.lastname: Lim
authors.forename: Duncan T
authors.initials: DT
authors.lastname: Odom
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Sulis
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Real
authors.forename: Adam
authors.initials: A
authors.lastname: Margolin
authors.forename: Kelly C
authors.initials: KC
authors.lastname: Barnes
authors.forename: Jennifer
authors.initials: J
authors.lastname: O'Neil
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Weng
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.forename: Francois
authors.initials: F
authors.lastname: Sigaux
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
authors.forename: Richard A
authors.initials: RA
authors.lastname: Young
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015202:Protein Engineering; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: C497761:NOTCH1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1