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Published online on November 17, 2006, 10.1073/pnas.0606108103
PNAS | November 28, 2006 | vol. 103 | no. 48 | 18261-18266


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BIOLOGICAL SCIENCES / MEDICAL SCIENCES
NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth

Teresa Palomero*, Wei Keat Lim{dagger}, Duncan T. Odom{ddagger}, Maria Luisa Sulis*, Pedro J. Real*, Adam Margolin{dagger}, Kelly C. Barnes*, Jennifer O'Neil§, Donna Neuberg, Andrew P. Weng||, Jon C. Aster**, Francois Sigaux{dagger}{dagger}, Jean Soulier{dagger}{dagger}, A. Thomas Look§, Richard A. Young{ddagger}, Andrea Califano{dagger}, and Adolfo A. Ferrando*,{ddagger},{ddagger}{ddagger}

*Institute for Cancer Genetics and {dagger}Joint Centers for Systems Biology, Columbia University, New York, NY 10032; {ddagger}Whitehead Institute, Cambridge, MA 02142; Departments of §Pediatric Oncology and Biostatistics, Dana–Farber Cancer Institute, Boston, MA 02115; ||Terry Fox Laboratory, BC Cancer Research Centre, Vancouver, BC, Canada V5Z 1L3; **Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115; and {dagger}{dagger}Genome Rearrangements and Cancer Group, Institut National de la Santé et de la Recherche Médicale U728, Saint-Louis Hospital, 75010 Paris, France

Edited by Richard A. Flavell, Yale University School of Medicine, New Haven, CT, and approved October 3, 2006 (received for review July 19, 2006)

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.

T cell lymphoblastic leukemia

Author contributions: T.P., J.C.A., F.S., J.S., A.T.L., R.A.Y., A.C., and A.A.F. designed research; T.P., W.K.L., D.T.O., M.L.S., P.J.R., A.M., K.C.B., J.O., F.S., J.S., and A.A.F. performed research; W.K.L., D.T.O., A.M., A.P.W., J.C.A., F.S., J.S., R.A.Y., and A.C. contributed new reagents/analytic tools; T.P., W.K.L., D.T.O., M.L.S., P.J.R., A.M., D.N., A.T.L., R.A.Y., A.C., and A.A.F. analyzed data; and T.P., A.C., and A.A.F. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS direct submission.

{ddagger}{ddagger}To whom correspondence should be addressed. E-mail: af2196{at}columbia.edu

© 2006 by The National Academy of Sciences of the USA


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