NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth.
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.
Palomero
Teresa
T
Institute for Cancer Genetics and Joint Centers for Systems Biology, Columbia University, New York, NY 10032, USA.
Lim
Wei Keat
WK
Odom
Duncan T
DT
Sulis
Maria Luisa
ML
Real
Pedro J
PJ
Margolin
Adam
A
Barnes
Kelly C
KC
O'Neil
Jennifer
J
Neuberg
Donna
D
Weng
Andrew P
AP
Aster
Jon C
JC
Sigaux
Francois
F
Soulier
Jean
J
Look
A Thomas
AT
Young
Richard A
RA
Califano
Andrea
A
Ferrando
Adolfo A
AA
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*
C497761:NOTCH1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1