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Blood, 1 December 2005, Vol. 106, No. 12, pp. 3898-3906. Prepublished online as a Blood First Edition Paper on August 23, 2005; DOI 10.1182/blood-2005-01-0355. This Article Full Text (PDF) All Versions of this Article: 2005-01-0355v1 106/12/3898    most recent Alert me when this article is cited Alert me if a correction is posted 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 Zweidler-McKay, P. A Articles by Pear, W. S Search for Related Content PubMed PubMed Citation Articles by Zweidler-McKay, P. A Articles by Pear, W. S Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 26, 2005 Accepted May 22, 2005 Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B cell malignancies Patrick A Zweidler-McKay, Yiping He, Lanwei Xu, Carlos G Rodriguez, Fredrick G Karnell, Andrea C Carpenter, Jon C Aster, David Allman, and Warren S Pear* Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA; Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA; Divisions of Hematology & Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA; Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA * Corresponding author; email: wpear{at}mail.med.upenn.edu. Although Notch receptor expression on malignant B-cells is widespread, the effect of Notch signaling in these cells is poorly understood. To investigate Notch signaling in B-cell malignancy, we assayed the effect of Notch activation in multiple murine and human B-cell tumors, representing both immature and mature subtypes. Expression of constitutively-active, truncated forms of the four mammalian Notch receptors (ICN1-4) inhibited growth and induced apoptosis in both murine and human B-cell lines, but not T-cell lines. Similar results were obtained in human precursor B-cell acute lymphoblastic leukemia lines when Notch activation was achieved by co-culture with fibroblasts expressing the Notch ligands Jagged1 or Jagged2. All four truncated Notch receptors, as well as the Jagged ligands, induced Hes1 transcription. Retroviral expression of Hes1 recapitulated the Notch effects suggesting that Hes1 is an important mediator of Notch-induced growth arrest and apoptosis in B-cells. Among the B-cell malignancies that were susceptible to Notch-mediated growth inhibition/apoptosis were mature B-cell and therapy-resistant B-cell malignancies including Hodgkins, myeloma and MLL-translocated cell lines. These results suggest that therapies capable of activating Notch/Hes1 signaling may have therapeutic potential in a wide range of human B-cell malignancies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. Zhang and P. J. Gallagher Mind bomb 1 regulation of cFLIP interactions Am J Physiol Cell Physiol, November 1, 2009; 297(5): C1275 - C1283. [Abstract] [Full Text] [PDF] S.-O. Yoon, X. Zhang, P. Berner, B. Blom, and Y. S. Choi Notch Ligands Expressed by Follicular Dendritic Cells Protect Germinal Center B Cells from Apoptosis J. Immunol., July 1, 2009; 183(1): 352 - 358. [Abstract] [Full Text] [PDF] H. Kohlhof, F. Hampel, R. Hoffmann, H. Burtscher, U. H. Weidle, M. Holzel, D. Eick, U. 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EWS-FLI1 Suppresses NOTCH-Activated p53 in Ewing's Sarcoma Cancer Res., September 1, 2008; 68(17): 7100 - 7109. [Abstract] [Full Text] [PDF] P. Zhang, Y. Yang, P. A. Zweidler-McKay, and D. P.M. Hughes Critical Role of Notch Signaling in Osteosarcoma Invasion and Metastasis Clin. Cancer Res., May 15, 2008; 14(10): 2962 - 2969. [Abstract] [Full Text] [PDF] K. G. Leong, K. Niessen, I. Kulic, A. Raouf, C. Eaves, I. Pollet, and A. Karsan Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin J. Exp. Med., November 26, 2007; 204(12): 2935 - 2948. [Abstract] [Full Text] [PDF] T. Maeda, T. Merghoub, R. M. Hobbs, L. Dong, M. Maeda, J. Zakrzewski, M. R.M. van den Brink, A. Zelent, H. Shigematsu, K. Akashi, et al. Regulation of B Versus T Lymphoid Lineage Fate Decision by the Proto-Oncogene LRF Science, May 11, 2007; 316(5826): 860 - 866. [Abstract] [Full Text] [PDF] V. Bolos, J. Grego-Bessa, and J. 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