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Blood, 1 August 2007, Vol. 110, No. 3, pp. 1004-1012. Prepublished online as a Blood First Edition Paper on April 19, 2007May 14, 2007; DOI 10.1182/blood-2007-01-066076. This Article Full Text (PDF) All Versions of this Article: blood-2007-01-066076v1 blood-2007-01-066076v2 110/3/1004    most recent Alert me when this article is cited Alert me if a correction is posted 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 Sargin, B. Articles by Serve, H. Search for Related Content PubMed PubMed Citation Articles by Sargin, B. Articles by Serve, H. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 4, 2007 Accepted March 30, 2007 Flt3-dependent transformation by inactivating c-Cbl mutations in AML Bulent Sargin, Chunaram Choudhary, Nicola Crosetto, Mirko H.H. Schmidt, Rebekka Grundler, Marion Rensinghoff, Christine Thiessen, Lara Tickenbrock, Joachim Schwable, Christian Brandts, Benjamin August, Steffen Koschmieder, Srinivasa Rao Bandi, Justus Duyster, Wolfgang E. Berdel, Carsten Muller-Tidow, Ivan Dikic, and Hubert Serve* Department of Medicine, Hematology and Oncology, and the Interdisciplinary Center for Clinical Research, University of Munster, Munster, Germany Institute of Biochemistry II, Goethe University Medical School, Frankfurt, Germany Department of Internal Medicine III, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany * Corresponding author; email: serve{at}uni-muenster.de. In acute myeloid leukemia (AML), mutational activation of the receptor tyrosine kinase (RTK) Flt3 is frequently involved in leukemic transformation. However, little is known about a possible role of highly expressed wild-type Flt3 in AML. The proto-oncogene c-Cbl is an important regulator of RTK signaling, acting through its ubiquitin ligase activity and as a platform for several signaling adaptor molecules. Here, we analyzed the role of c-Cbl in Flt3 signal transduction and myeloid transformation. C-Cbl physically interacted with Flt3 and was tyrosine phosphorylated in the presence of Flt3-ligand (FL). Overexpression of a dominant negative form of c-Cbl (Cbl-70Z) inhibited FL-induced Flt3 ubiquitylation and internalization, indicating involvement of c-Cbl in Flt3 signaling. DNA sequencing of AML bone marrow revealed a case with a c-Cbl point mutation (Cbl-R420Q). Cbl-R420Q inhibited Flt3 internalization and ubiquitylation. Co-expression of Cbl-R420Q or Cbl-70Z with Flt3 induced cytokine-independent growth and survival of 32Dcl3 cells in the absence of FL. Also, the mutant Cbl proteins altered the amplitude and duration of Flt3-dependent signaling events. Our results indicate an important role of Cbl proteins in Flt3 signal modulation. Also, the data suggest a novel mechanism of leukemic transformation in AML by mutational inactivation of negative RTK regulators. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Partners in AML: Flt3 and c-Cbl Wallace Y. Langdon Blood 2007 110: 793-794. [Full Text] [PDF] This article has been cited by other articles: M. R. McKeller, R. S. Robetorye, P. L. M. Dahia, and R. C. T. Aguiar Integrity of the CBL gene in mature B-cell malignancies Blood, November 5, 2009; 114(19): 4321 - 4322. [Full Text] [PDF] S. R. Bandi, C. Brandts, M. Rensinghoff, R. Grundler, L. Tickenbrock, G. Kohler, J. Duyster, W. E. 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Recher A critical role for Lyn in acute myeloid leukemia Blood, February 15, 2008; 111(4): 2269 - 2279. [Abstract] [Full Text] [PDF] M. A. Caligiuri, R. Briesewitz, J. Yu, L. Wang, M. Wei, K. J. Arnoczky, T. B. Marburger, J. Wen, D. Perrotti, C. D. Bloomfield, et al. Novel c-CBL and CBL-b ubiquitin ligase mutations in human acute myeloid leukemia Blood, August 1, 2007; 110(3): 1022 - 1024. [Abstract] [Full Text] [PDF]

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