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Prepublished online as a Blood First Edition Paper on December 19, 2002; DOI 10.1182/blood-2002-06-1800. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-06-1800v1 101/8/3188    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 Sohal, J. Articles by Kogan, S. C. Search for Related Content PubMed PubMed Citation Articles by Sohal, J. Articles by Kogan, S. C. Related Collections Oncogenes and Tumor Suppressors Signal Transduction Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 April 2003, Vol. 101, No. 8, pp. 3188-3197 NEOPLASIA A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657 Jastinder Sohal, Vernon T. Phan, Philip V. Chan, Elizabeth M. Davis, Bhumi Patel, Louise M. Kelly, Tinya J. Abrams, Anne Marie O'Farrell, D. Gary Gilliland, Michelle M. Le Beau, and Scott C. Kogan From the Comprehensive Cancer Center and the Department of Laboratory Medicine, University of California, San Francisco; Section of Hematology/Oncology, University of Chicago, IL; Division of Hematology/Oncology, Brigham and Women's Hospital and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA; and Sugen Inc, South San Francisco, CA. The PML-RAR fusion protein is central to the pathogenesis of acute promyelocytic leukemia (APL). Expression of this protein in transgenic mice initiates myeloid leukemias with features of human APL, but only after a long latency (8.5 months in MRP8 PML-RARA mice). Thus, additional changes contribute to leukemic transformation. Activating mutations of the FLT3 receptor tyrosine kinase are common in human acute myeloid leukemias and are frequent in human APL. To assess how activating mutations of FLT3 contribute to APL pathogenesis and impact therapy, we used retroviral transduction to introduce an activated allele of FLT3 into control and MRP8 PML-RARA transgenic bone marrow. Activated FLT3 cooperated with PML-RAR to induce leukemias in 62 to 299 days (median latency, 105 days). In contrast to the leukemias that arose spontaneously in MRP8 PML-RARA mice, the activated FLT3/PML-RAR leukemias were characterized by leukocytosis, similar to human APL with FLT3 mutations. Cytogenetic analysis revealed clonal karyotypic abnormalities, which may contribute to pathogenesis or progression. SU11657, a selective, oral, multitargeted tyrosine kinase inhibitor that targets FLT3, cooperated with all-trans retinoic acid to rapidly cause regression of leukemia. Our results suggest that the acquisition of FLT3 mutations by cells with a pre-existing t(15;17) is a frequent pathway to the development of APL. Our findings also indicate that APL patients with FLT3 mutations may benefit from combination therapy with all-trans retinoic acid plus an FLT3 inhibitor. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Z.-Y. Wang and Z. Chen Acute promyelocytic leukemia: from highly fatal to highly curable Blood, March 1, 2008; 111(5): 2505 - 2515. [Abstract] [Full Text] [PDF] I. T. Chan, J. L. Kutok, I. R. Williams, S. Cohen, S. Moore, H. 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