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Blood, 1 July 2007, Vol. 110, No. 1, pp. 278-286. Prepublished online as a Blood First Edition Paper on March 15, 2007; DOI 10.1182/blood-2006-08-039883. This Article Full Text Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2006-08-039883v1 110/1/278    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chan, S. M. Articles by Utz, P. J. Search for Related Content PubMed PubMed Citation Articles by Chan, S. M. Articles by Utz, P. J. Related Collections Neoplasia Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia Steven M. Chan1, Andrew P. Weng2, Robert Tibshirani3, Jon C. Aster4, and Paul J. Utz1 1 Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA; 2 Department of Pathology, Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, BC; 3 Department of Biostatistics, Stanford University, Stanford, CA; 4 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA Constitutive Notch activation is required for the proliferation of a subgroup of T-cell acute lymphoblastic leukemia (T-ALL). Downstream pathways that transmit pro-oncogenic signals are not well characterized. To identify these pathways, protein microarrays were used to profile the phosphorylation state of 108 epitopes on 82 distinct signaling proteins in a panel of 13 T-cell leukemia cell lines treated with a gamma-secretase inhibitor (GSI) to inhibit Notch signals. The microarray screen detected GSI-induced hypophosphorylation of multiple signaling proteins in the mTOR pathway. This effect was rescued by expression of the intracellular domain of Notch and mimicked by dominant negative MAML1, confirming Notch specificity. Withdrawal of Notch signals prevented stimulation of the mTOR pathway by mitogenic factors. These findings collectively suggest that the mTOR pathway is positively regulated by Notch in T-ALL cells. The effect of GSI on the mTOR pathway was independent of changes in phosphatidylinositol-3 kinase and Akt activity, but was rescued by expression of c-Myc, a direct transcriptional target of Notch, implicating c-Myc as an intermediary between Notch and mTOR. T-ALL cell growth was suppressed in a highly synergistic manner by simultaneous treatment with the mTOR inhibitor rapamycin and GSI, which represents a rational drug combination for treating this aggressive human malignancy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. R. Mansour, M. L. Sulis, V. Duke, L. Foroni, S. Jenkinson, K. Koo, C. G. Allen, R. E. Gale, G. Buck, S. Richards, et al. Prognostic Implications of NOTCH1 and FBXW7 Mutations in Adults With T-Cell Acute Lymphoblastic Leukemia Treated on the MRC UKALLXII/ECOG E2993 Protocol J. Clin. Oncol., September 10, 2009; 27(26): 4352 - 4356. [Abstract] [Full Text] [PDF] M. El-Salem, P. N. Raghunath, M. Marzec, X. Liu, M. Kasprzycka, E. Robertson, and M. A. Wasik Activation of mTORC1 Signaling Pathway in AIDS-Related Lymphomas Am. J. Pathol., August 1, 2009; 175(2): 817 - 824. [Abstract] [Full Text] [PDF] K. Cullion, K. M. Draheim, N. 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