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1 Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA; 2 Department of Pathology and Lab Medicine, Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada; 3 Department of Pathology and Lab Medicine, Abramson Family Cancer Research Institute, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; 4 University of Pennsylvania Bioinformatics Core, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; 5 Molecular Pharmacololgy and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA; 6 Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA; 7 Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, California 94305, USA
Human acute T-cell lymphoblastic leukemias and lymphomas (T-ALL) are commonly associated with gain-of-function mutations in Notch1 that contribute to T-ALL induction and maintenance. Starting from an expression-profiling screen, we identified c-myc as a direct target of Notch1 in Notch-dependent T-ALL cell lines, in which Notch accounts for the majority of c-myc expression. In functional assays, inhibitors of c-myc interfere with the progrowth effects of activated Notch1, and enforced expression of c-myc rescues multiple Notch1-dependent T-ALL cell lines from Notch withdrawal. The existence of a Notch1–c-myc signaling axis was bolstered further by experiments using c-myc-dependent murine T-ALL cells, which are rescued from withdrawal of c-myc by retroviral transduction of activated Notch1. This Notch1-mediated rescue is associated with the up-regulation of endogenous murine c-myc and its downstream transcriptional targets, and the acquisition of sensitivity to Notch pathway inhibitors. Additionally, we show that primary murine thymocytes at the DN3 stage of development depend on ligand-induced Notch signaling to maintain c-myc expression. Together, these data implicate c-myc as a developmentally regulated direct downstream target of Notch1 that contributes to the growth of T-ALL cells.
[Keywords: Notch; Myc; leukemia; T cell; transformation]
Received February 17, 2006; revised version accepted June 6, 2006.
E-MAIL jaster{at}rics.bwh.harvard.edu; FAX (617) 264-5169.
10 E-MAIL wpear{at}mail.med.upenn.edu; FAX (215) 746-6725.
Supplemental material is available at http://www.genesdev.org.
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1450406
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