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Blood, 15 February 2006, Vol. 107, No. 4, pp. 1617-1623. Prepublished online as a Blood First Edition Paper on October 27, 2005; DOI 10.1182/blood-2005-08-3254. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-08-3254v1 107/4/1617    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 Wan, W. Articles by Cheng, M. Search for Related Content PubMed PubMed Citation Articles by Wan, W. Articles by Cheng, M. Related Collections Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Anaplastic lymphoma kinase activity is essential for the proliferation and survival of anaplastic large-cell lymphoma cells Weihua Wan, Mark S. Albom, Lihui Lu, Matthew R. Quail, Nadine C. Becknell, Linda R. Weinberg, Dandu R. Reddy, Beverly P. Holskin, Thelma S. Angeles, Ted L. Underiner, Sheryl L. Meyer, Robert L. Hudkins, Bruce D. Dorsey, Mark A. Ator, Bruce A. Ruggeri, and Mangeng Cheng From the Oncology, Lead Discovery and Profiling, and Chemistry, Cephalon Inc, West Chester, PA. The roles of aberrant expression of constitutively active ALK chimeric proteins in the pathogenesis of anaplastic large-cell lymphoma (ALCL) have been well defined; nevertheless, the notion that ALK is a molecular target for the therapeutic modulation of ALK+ ALCL has not been validated thus far. Select fused pyrrolocarbazole (FP)–derived small molecules with ALK inhibitory activity were used as pharmacologic tools to evaluate whether functional ALK is essential for the proliferation and survival of ALK+ ALCL cells in culture. These compounds inhibited interleukin 3 (IL-3)–independent proliferation of BaF3/NPM-ALK cells in an ALK inhibition-dependent manner and significantly blocked colony formation in agar of mouse embryonic fibroblast (MEF) cells harboring NPM-ALK. Inhibition of NPM-ALK phosphorylation in the ALK+ ALCL-derived cell lines resulted in significant inhibition of cell proliferation and induction of apoptotic-cell death, while having marginal effects on the proliferation and survival of K562, an ALK- leukemia cell line. ALK inhibition resulted in cell-cycle G1 arrest and inactivation of ERK1/2, STAT3, and AKT signaling pathways. Potent and selective ALK inhibitors may have therapeutic application for ALK+ ALCL and possibly other solid and hematologic tumors in which ALK activation is implicated in their pathogenesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Ambrogio, C. Martinengo, C. Voena, F. Tondat, L. Riera, P. F. di Celle, G. Inghirami, and R. Chiarle NPM-ALK Oncogenic Tyrosine Kinase Controls T-Cell Identity by Transcriptional Regulation and Epigenetic Silencing in Lymphoma Cells Cancer Res., November 15, 2009; 69(22): 8611 - 8619. [Abstract] [Full Text] [PDF] L. Passoni, L. Longo, P. Collini, A. M. L. Coluccia, F. Bozzi, M. Podda, A. Gregorio, C. Gambini, A. Garaventa, V. Pistoia, et al. Mutation-Independent Anaplastic Lymphoma Kinase Overexpression in Poor Prognosis Neuroblastoma Patients Cancer Res., September 15, 2009; 69(18): 7338 - 7346. [Abstract] [Full Text] [PDF] E. Lin, L. Li, Y. Guan, R. Soriano, C. 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