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Blood, 15 June 2008, Vol. 111, No. 12, pp. 5663-5671. Prepublished online as a Blood First Edition Paper on November 5, 2007; DOI 10.1182/blood-2007-04-083402. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-04-083402v1 111/12/5663    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 Hexner, E. O. Articles by Dobrzanski, P. Search for Related Content PubMed PubMed Citation Articles by Hexner, E. O. Articles by Dobrzanski, P. Related Collections Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders Elizabeth O. Hexner1, Cynthia Serdikoff2, Mahfuza Jan2, Cezary R. Swider1, Candy Robinson2, Shi Yang2, Thelma Angeles2, Stephen G. Emerson1, Martin Carroll1, Bruce Ruggeri2, and Pawel Dobrzanski2 1 Division of Hematology and Oncology, University of Pennsylvania, Philadelphia; and 2 Cephalon, West Chester, PA Recent studies have demonstrated that patients with myeloproliferative disorders (MPDs) frequently have acquired activating mutations in the JAK2 tyrosine kinase. A multikinase screen determined that lestaurtinib (formerly known as CEP-701) inhibits wild type JAK2 kinase activity with a concentration that inhibits response by 50% (IC50) of 1 nM in vitro. We hypothesized that lestaurtinib would inhibit mutant JAK2 kinase activity and suppress the growth of cells from patients with MPDs. We found that lestaurtinib inhibits the growth of HEL92.1.7 cells, which are dependent on mutant JAK2 activity for growth in vitro and in xenograft models. Erythroid cells expanded from primary CD34+ cells from patients with MPDs were inhibited by lestaurtinib at concentrations of 100 nM or more in 15 of 18 subjects, with concomitant inhibition of phosphorylation of STAT5 and other downstream effectors of JAK2. By contrast, growth of erythroid cells derived from 3 healthy controls was not significantly inhibited. These results demonstrate that lestaurtinib, in clinically achievable concentrations, inhibits proliferation and JAK2/STAT5 signaling in cells from patients with MPDs, and therefore holds promise as a therapeutic agent for patients with these disorders. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Can we control JAK? Radek C. Skoda Blood 2008 111: 5419-5420. [Full Text] [PDF] This article has been cited by other articles: S. Y. Cheranov, D. Wang, V. Kundumani-Sridharan, M. Karpurapu, Q. Zhang, K. R. Chava, and G. N. Rao The 15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis requires Janus kinase 2-signal transducer and activator of transcription-5B-dependent expression of interleukin-8 Blood, June 4, 2009; 113(23): 6023 - 6033. [Abstract] [Full Text] [PDF] A. M. Vannucchi, P. Guglielmelli, and A. Tefferi Advances in Understanding and Management of Myeloproliferative Neoplasms CA Cancer J Clin, May 1, 2009; 59(3): 171 - 191. [Abstract] [Full Text] [PDF] M. Skarica, T. Wang, E. McCadden, D. Kardian, P. A. Calabresi, D. Small, and K. A. Whartenby Signal Transduction Inhibition of APCs Diminishes Th17 and Th1 Responses in Experimental Autoimmune Encephalomyelitis J. Immunol., April 1, 2009; 182(7): 4192 - 4199. [Abstract] [Full Text] [PDF] S. Verstovsek New Therapeutic Options for Myelofibrosis ASCO Educational Book, January 1, 2009; 2009(1): 426 - 429. [Abstract] [Full Text] [PDF]

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