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Blood, 1 January 2004, Vol. 103, No. 1, pp. 267-274. Prepublished online as a Blood First Edition Paper on September 11, 2003; DOI 10.1182/blood-2003-06-1969. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-06-1969v1 103/1/267    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 Zheng, R. Articles by Small, D. Search for Related Content PubMed PubMed Citation Articles by Zheng, R. Articles by Small, D. Related Collections Neoplasia Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells Rui Zheng, Mark Levis, Obdulio Piloto, Patrick Brown, Brenda R. Baldwin, Norbert C. Gorin, Miloslav Beran, Zhenping Zhu, Dale Ludwig, Dan Hicklin, Larry Witte, Yiwen Li, and Donald Small From the Johns Hopkins University School of Medicine, Oncology, Pediatrics, Baltimore, MD; the Department of Hematology, Hospital Saint-Antoine, Paris, France; the Department of Leukemia, MD Anderson Cancer Center, Houston, TX; and ImClone Systems, Inc, New York, NY. The FLT3 receptor tyrosine kinase is highly expressed in most acute leukemias and frequently mutated in acute myeloid leukemia (AML). The mutated form of the receptor is constitutively activated and known to play an important role in AML, but the activation state of the overexpressed wild-type (wt) receptor is, at present, unknown. In this study, we examined the activation state of the wild-type receptor in AML. We found that the wild-type receptor was constitutively phosphorylated/activated in 8 of 12 primary AML samples and 4 of 13 leukemia cell lines. To explain why wtFLT3 is often activated, we investigated the expression of its ligand, FL, by these same cells. Coexpression of FL with FLT3 was a universal finding in both primary AML samples and leukemic-derived cell lines. To further prove that autocrine signaling was accounting for the activation, we showed that conditioned media but not fresh media was able to activate FLT3. In addition, an antibody that blocks binding of ligand to the receptor blocks FLT3 activation. Finally, depletion of FL from conditioned media is able to block the activation of FLT3. Taken together, these findings represent strong evidence that wtFLT3 is often constitutively activated in AML and thus, like its mutated form, might contribute to the altered signaling that characterizes leukemogenesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Shiotsu, H. Kiyoi, Y. Ishikawa, R. Tanizaki, M. Shimizu, H. Umehara, K. Ishii, Y. Mori, K. Ozeki, Y. Minami, et al. KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation Blood, August 20, 2009; 114(8): 1607 - 1617. [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. Pelus Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal tandem duplication of Flt3 Blood, July 9, 2009; 114(2): 394 - 403. 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