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Blood, 15 July 2005, Vol. 106, No. 2, pp. 673-680. Prepublished online as a Blood First Edition Paper on March 29, 2005; DOI 10.1182/blood-2004-05-1902. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-05-1902v1 106/2/673    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 Levis, M. Articles by Small, D. Search for Related Content PubMed PubMed Citation Articles by Levis, M. Articles by Small, D. Related Collections Neoplasia Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Internal tandem duplications of the FLT3 gene are present in leukemia stem cells Mark Levis, Kathleen M. Murphy, Rosalyn Pham, Kyu-Tae Kim, Adam Stine, Li Li, Ian McNiece, B. Douglas Smith, and Donald Small From the Departments of Oncology, Pathology, and Pediatrics, Kimmel Cancer Center at Johns Hopkins, Baltimore, MD. Internal tandem duplication mutations of the FLT3 gene (FLT3/ITD mutations) are the most frequent molecular abnormality in acute myeloid leukemia (AML) and are associated with a poor overall survival. While the normal FLT3 receptor is expressed in early hematopoietic progenitor cells, it has not been determined whether FLT3 mutations are present in the leukemic stem cells. In this study, we sorted primary AML samples into stem cell-enriched CD34+/CD38- fractions and then analyzed the sorted and unsorted cells for the FLT3 mutant-wild-type ratio. In each case, the FLT3 mutant-wild-type ratio was not changed by selection of CD34+/CD38- cells, implying that the mutations are present in the leukemic stem cells. We used the stem cell-enriched fraction to engraft nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice and then confirmed that the FLT3/ITD mutation was present in the resultant engrafted marrow. As a final test of the importance of FLT3/ITD signaling in this engraftment model, we used a small molecule FLT3 inhibitor, CEP-701, to inhibit engraftment of FLT3/ITD stem cells. Taken together, these experiments establish that the FLT3/ITD mutations are present in leukemia stem cells, and that FLT3 inhibitors may have activity against these cells. (Blood. 2005;106:673-680) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: W. Zhang, M. Konopleva, Y.-x. Shi, T. McQueen, D. Harris, X. Ling, Z. Estrov, A. Quintas-Cardama, D. Small, J. Cortes, et al. Mutant FLT3: A Direct Target of Sorafenib in Acute Myelogenous Leukemia J Natl Cancer Inst, February 6, 2008; 100(3): 184 - 198. [Abstract] [Full Text] [PDF] M. L. Guzman, X. Li, C. A. Corbett, R. M. Rossi, T. Bushnell, J. L. Liesveld, J. Hebert, F. Young, and C. T. Jordan Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8) Blood, December 15, 2007; 110(13): 4436 - 4444. [Abstract] [Full Text] [PDF] S. Chumsri, W. Matsui, and A. M. Burger Therapeutic Implications of Leukemic Stem Cell Pathways Clin. Cancer Res., November 15, 2007; 13(22): 6549 - 6554. [Abstract] [Full Text] [PDF] S. Vempati, C. Reindl, S. K. 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Levis FLT3: the root of the problem Blood, October 15, 2006; 108(8): 2501 - 2502. [Full Text] [PDF] D. Small FLT3 Mutations: Biology and Treatment Hematology, January 1, 2006; 2006(1): 178 - 184. [Abstract] [Full Text] [PDF] R. E. Gale, R. Hills, A. R. Pizzey, P. D. Kottaridis, D. Swirsky, A. F. Gilkes, E. Nugent, K. I. Mills, K. Wheatley, E. Solomon, et al. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia Blood, December 1, 2005; 106(12): 3768 - 3776. [Abstract] [Full Text] [PDF]

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