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This Article Full Text Full Text (PDF) 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 Kelly, L. M. Articles by Gilliland, D. G. Search for Related Content PubMed PubMed Citation Articles by Kelly, L. M. Articles by Gilliland, D. G. Related Collections Neoplasia Related Letter in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 January 2002, Vol. 99, No. 1, pp. 310-318 NEOPLASIA FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model Louise M. Kelly, Qing Liu, Jeffrey L. Kutok, Ifor R. Williams, Christina L. Boulton, and D. Gary Gilliland From the Division of Hematology/Oncology, Department of Pathology, Brigham and Women's Hospital, and the Howard Hughes Medical Institute, Harvard Medical School, Boston, MA; and Department of Pathology, Emory University, Atlanta, GA. FLT3 receptor tyrosine kinase is expressed on lymphoid and myeloid progenitors in the hematopoietic system. Activating mutations in FLT3 have been identified in approximately 30% of patients with acute myelogenous leukemia, making it one of the most common mutations observed in this disease. Frequently, the mutation is an in-frame internal tandem duplication (ITD) in the juxtamembrane region that results in constitutive activation of FLT3, and confers interleukin-3 (IL-3)-independent growth to Ba/F3 and 32D cells. FLT3-ITD mutants were cloned from primary human leukemia samples and assayed for transformation of primary hematopoietic cells using a murine bone marrow transplantation assay. FLT3-ITDs induced an oligoclonal myeloproliferative disorder in mice, characterized by splenomegaly and leukocytosis. The myeloproliferative phenotype, which was associated with extramedullary hematopoiesis in the spleen and liver, was confirmed by histopathologic and flow cytometric analysis. The disease latency of 40 to 60 days with FLT3-ITDs contrasted with wild-type FLT3 and enhanced green fluorescent protein (EGFP) controls, which did not develop hematologic disease (> 200 days). These results demonstrate that FLT3-ITD mutant proteins are sufficient to induce a myeloproliferative disorder, but are insufficient to recapitulate the AML phenotype observed in humans. Additional mutations that impair hematopoietic differentiation may be required for the development of FLT3-ITD-associated acute myeloid leukemias. This model system should be useful to assess the contribution of additional cooperating mutations and to evaluate specific FLT3 inhibitors in vivo. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Letter in Blood Online: Platelet-dependent action of high-dose factor VIIa Maureane Hoffman, Dougald M. Monroe, Harold R. Roberts, Kenneth G. Mann, and Saulius Butenas Blood 2002 100: 364-366. [Full Text] [PDF] This article has been cited by other articles: H. Haeno, R. L. Levine, D. G. Gilliland, and F. Michor A progenitor cell origin of myeloid malignancies PNAS, September 29, 2009; 106(39): 16616 - 16621. [Abstract] [Full Text] [PDF] S. Fukuda, P. Singh, A. Moh, M. Abe, E. M. Conway, H. S. Boswell, S. Yamaguchi, X.-Y. Fu, and L. M. 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[Abstract] [Full Text] [PDF] A.-M. O'Farrell, J. M. Foran, W. Fiedler, H. Serve, R. L. Paquette, M. A. Cooper, H. A. Yuen, S. G. Louie, H. Kim, S. Nicholas, et al. An Innovative Phase I Clinical Study Demonstrates Inhibition of FLT3 Phosphorylation by SU11248 in Acute Myeloid Leukemia Patients Clin. Cancer Res., November 15, 2003; 9(15): 5465 - 5476. [Abstract] [Full Text] [PDF] C. M. Zwaan, S. Meshinchi, J. P. Radich, A. J. P. Veerman, D. R. Huismans, L. Munske, M. Podleschny, K. Hahlen, R. Pieters, M. Zimmermann, et al. FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance Blood, October 1, 2003; 102(7): 2387 - 2394. [Abstract] [Full Text] [PDF] S. Wong, J. McLaughlin, D. Cheng, K. Shannon, L. Robb, and O. N. Witte IL-3 receptor signaling is dispensable for BCR-ABL-induced myeloproliferative disease PNAS, September 30, 2003; 100(20): 11630 - 11635. [Abstract] [Full Text] [PDF] K. Murata, H. Kumagai, T. Kawashima, K. Tamitsu, M. Irie, H. Nakajima, S. Suzu, M. Shibuya, S. Kamihira, T. Nosaka, et al. Selective Cytotoxic Mechanism of GTP-14564, a Novel Tyrosine Kinase Inhibitor in Leukemia Cells Expressing a Constitutively Active Fms-like Tyrosine Kinase 3 (FLT3) J. Biol. Chem., August 29, 2003; 278(35): 32892 - 32898. [Abstract] [Full Text] [PDF] M. M. Le Beau, E. M. Davis, B. Patel, V. T. Phan, J. Sohal, and S. C. Kogan Recurring chromosomal abnormalities in leukemia in PML-RARA transgenic mice identify cooperating events and genetic pathways to acute promyelocytic leukemia Blood, August 1, 2003; 102(3): 1072 - 1074. [Abstract] [Full Text] [PDF] H. Karsunky, M. Merad, A. Cozzio, I. L. Weissman, and M. G. Manz Flt3 Ligand Regulates Dendritic Cell Development from Flt3+ Lymphoid and Myeloid-committed Progenitors to Flt3+ Dendritic Cells In Vivo J. Exp. Med., July 21, 2003; 198(2): 305 - 313. [Abstract] [Full Text] [PDF] R. Grundler, C. Thiede, C. Miething, C. Steudel, C. Peschel, and J. Duyster Sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor Blood, July 15, 2003; 102(2): 646 - 651. [Abstract] [Full Text] [PDF] K. Spiekermann, K. Bagrintseva, R. Schwab, K. Schmieja, and W. Hiddemann Overexpression and Constitutive Activation of FLT3 Induces STAT5 Activation in Primary Acute Myeloid Leukemia Blast Cells Clin. Cancer Res., June 1, 2003; 9(6): 2140 - 2150. [Abstract] [Full Text] [PDF] A.-M. O'Farrell, T. J. Abrams, H. A. Yuen, T. J. Ngai, S. G. Louie, K. W. H. Yee, L. M. Wong, W. Hong, L. B. Lee, A. Town, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo Blood, May 1, 2003; 101(9): 3597 - 3605. [Abstract] [Full Text] [PDF] M. Mizuki, J. Schwable, C. Steur, C. Choudhary, S. Agrawal, B. Sargin, B. Steffen, I. Matsumura, Y. Kanakura, F. D. Bohmer, et al. Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations Blood, April 15, 2003; 101(8): 3164 - 3173. [Abstract] [Full Text] [PDF] J. Sohal, V. T. Phan, P. V. Chan, E. M. Davis, B. Patel, L. M. Kelly, T. J. Abrams, A. M. O'Farrell, D. G. Gilliland, M. M. Le Beau, et al. A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657 Blood, April 15, 2003; 101(8): 3188 - 3197. [Abstract] [Full Text] [PDF] K. Spiekermann, R. J. Dirschinger, R. Schwab, K. Bagrintseva, F. Faber, C. Buske, S. Schnittger, L. M. Kelly, D. G. Gilliland, and W. Hiddemann The protein tyrosine kinase inhibitor SU5614 inhibits FLT3 and induces growth arrest and apoptosis in AML-derived cell lines expressing a constitutively activated FLT3 Blood, February 15, 2003; 101(4): 1494 - 1504. [Abstract] [Full Text] [PDF] F. Ravandi, M. Talpaz, and Z. Estrov Modulation of Cellular Signaling Pathways: Prospects for Targeted Therapy in Hematological Malignancies Clin. Cancer Res., February 1, 2003; 9(2): 535 - 550. [Abstract] [Full Text] [PDF] B. Lowenberg, J. D. Griffin, and M. S. Tallman Acute Myeloid Leukemia and Acute Promyelocytic Leukemia Hematology, January 1, 2003; 2003(1): 82 - 101. [Abstract] [Full Text] [PDF] Z. Qian, A. A. Fernald, L. A. Godley, R. A. Larson, and M. M. Le Beau Expression profiling of CD34+ hematopoietic stem/ progenitor cells reveals distinct subtypes of therapy-related acute myeloid leukemia PNAS, November 12, 2002; 99(23): 14925 - 14930. [Abstract] [Full Text] [PDF] K. Spiekermann, K. Bagrintseva, C. Schoch, T. Haferlach, W. Hiddemann, and S. Schnittger A new and recurrent activating length mutation in exon 20 of the FLT3 gene in acute myeloid leukemia Blood, October 16, 2002; 100(9): 3423 - 3425. [Abstract] [Full Text] [PDF] K. W. H. Yee, A. M. O'Farrell, B. D. Smolich, J. M. Cherrington, G. McMahon, C. L. Wait, L. S. McGreevey, D. J. Griffith, and M. C. Heinrich SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase Blood, September 26, 2002; 100(8): 2941 - 2949. [Abstract] [Full Text] [PDF] D. G. Gilliland and J. D. Griffin The roles of FLT3 in hematopoiesis and leukemia Blood, August 13, 2002; 100(5): 1532 - 1542. [Abstract] [Full Text] [PDF] F. M. Abu-Duhier, A. C. Goodeve, G. A. Wilson, R. S. Carr, I. R. Peake, and J. T. Reilly FLT3 internal tandem duplication mutations are rare in agnogenic myeloid metaplasia Blood, June 17, 2002; 100(1): 364 - 364. [Full Text] [PDF] D. G. B. Leonard, L. B. Travis, K. Addya, G. M. Dores, E. J. Holowaty, K. Bergfeldt, D. Malkin, B. A. Kohler, C. F. Lynch, T. Wiklund, et al. p53 Mutations in Leukemia and Myelodysplastic Syndrome after Ovarian Cancer Clin. Cancer Res., May 1, 2002; 8(5): 973 - 985. [Abstract] [Full Text] [PDF]

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