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Blood, 1 November 2005, Vol. 106, No. 9, pp. 3206-3213. Prepublished online as a Blood First Edition Paper on July 19, 2005; DOI 10.1182/blood-2005-05-1932. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-05-1932v1 106/9/3206    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 Stover, E. H. Articles by Gilliland, D. G. Search for Related Content PubMed PubMed Citation Articles by Stover, E. H. Articles by Gilliland, D. G. Related Collections Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Related Letter in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA The small molecule tyrosine kinase inhibitor AMN107 inhibits TEL-PDGFR and FIP1L1-PDGFR in vitro and in vivo Elizabeth H. Stover, Jing Chen, Benjamin H. Lee, Jan Cools, Elizabeth McDowell, Jennifer Adelsperger, Dana Cullen, Allison Coburn, Sandra A. Moore, Rachel Okabe, Doriano Fabbro, Paul W. Manley, James D. Griffin, and D. Gary Gilliland From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA; the Department of Genetics, Harvard Medical School, Boston, MA; the Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA; the Department of Pathology, Brigham and Women's Hospital, Boston, MA; the Department of Human Genetics, University of Leuven-Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium; the Novartis Institutes for Biomedical Research, Basel, Switzerland; the Dana-Farber Cancer Institute, Boston, MA; and the Howard Hughes Medical Institute, Harvard Medical School, Boston, MA. AMN107 is a small molecule tyrosine kinase inhibitor developed, in the first instance, as a potent inhibitor of breakpoint cluster region-abelson (BCR-ABL). We tested its effectiveness against fusion tyrosine kinases TEL–platelet-derived growth factor receptor (TEL-PDGFR) and FIP1-like-1 (FIP1L1)–PDGFR, which cause chronic myelomonocytic leukemia and hypereosinophilic syndrome, respectively. In vitro, AMN107 inhibited proliferation of Ba/F3 cells transformed by both TEL-PDGFR and FIP1L1-PDGFR with IC50 (inhibitory concentration 50%) values less than 25 nM and inhibited phosphorylation of the fusion kinases and their downstream signaling targets. The imatinib mesylate–resistant mutant TEL-PDGFR T681I was sensitive to AMN107, whereas the analogous mutation in FIP1L1-PDGFR, T674I, was resistant. In an in vivo bone marrow transplantation assay, AMN107 effectively treated myeloproliferative disease induced by TEL-PDGFR and FIP1L1-PDGFR, significantly increasing survival and disease latency and reducing disease severity as assessed by histopathology and flow cytometry. In summary, AMN107 can inhibit myeloid proliferation driven by TEL-PDGFR and FIP1L1-PDGFR and may be a useful drug for treatment of patients with myeloproliferative disease who harbor these kinase fusions. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Letter in Blood Online: The FIP1L1-PDGFRA T674I mutation can be inhibited by the tyrosine kinase inhibitor AMN107 (nilotinib) Nikolas von Bubnoff, Sivahari Prasad Gorantla, Silvia Thöne, Christian Peschel, Justus Duyster, Elizabeth H. Stover, Jan Cools, and D. Gary Gilliland Blood 2006 107: 4970-4972. [Full Text] [PDF] This article has been cited by other articles: K. Fukushima, I. Matsumura, S. Ezoe, M. Tokunaga, M. Yasumi, Y. Satoh, H. Shibayama, H. Tanaka, A. Iwama, and Y. Kanakura FIP1L1-PDGFR{alpha} Imposes Eosinophil Lineage Commitment on Hematopoietic Stem/Progenitor Cells J. Biol. Chem., March 20, 2009; 284(12): 7719 - 7732. [Abstract] [Full Text] [PDF] H. G. Jorgensen, E. K. Allan, N. E. Jordanides, J. C. Mountford, and T. L. Holyoake Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells Blood, May 1, 2007; 109(9): 4016 - 4019. [Abstract] [Full Text] [PDF] E. Lierman and J. Cools ETV6 and PDGFRB: a license to fuse Haematologica, February 1, 2007; 92(2): 145 - 147. [Full Text] [PDF] E. Lierman, C. Folens, E. H. Stover, N. Mentens, H. Van Miegroet, W. Scheers, M. Boogaerts, P. Vandenberghe, P. Marynen, and J. Cools Sorafenib is a potent inhibitor of FIP1L1-PDGFR{alpha} and the imatinib-resistant FIP1L1-PDGFR{alpha} T674I mutant Blood, August 15, 2006; 108(4): 1374 - 1376. [Abstract] [Full Text] [PDF] D. L. White, V. A. Saunders, P. Dang, J. Engler, A. C. W. Zannettino, A. C. Cambareri, S. R. Quinn, P. W. Manley, and T. P. Hughes OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib Blood, July 15, 2006; 108(2): 697 - 704. [Abstract] [Full Text] [PDF] N. von Bubnoff, S. P. Gorantla, S. Thone, C. Peschel, J. Duyster, E. H. Stover, J. Cools, and D. G. Gilliland The FIP1L1-PDGFRA T674I mutation can be inhibited by the tyrosine kinase inhibitor AMN107 (nilotinib) Blood, June 15, 2006; 107(12): 4970 - 4972. [Full Text] [PDF] Y. Yamada, M. E. Rothenberg, A. W. Lee, H. S. Akei, E. B. Brandt, D. A. Williams, and J. A. Cancelas The FIP1L1-PDGFRA fusion gene cooperates with IL-5 to induce murine hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL)-like disease Blood, May 15, 2006; 107(10): 4071 - 4079. [Abstract] [Full Text] [PDF]

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