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Blood, 5 November 2009, Vol. 114, No. 19, pp. 4197-4208. Prepublished online as a Blood First Edition Paper on September 4, 2009; DOI 10.1182/blood-2008-12-190934. This Article Full Text Full Text (PDF) Supplemental Appendix and Figures All Versions of this Article: blood-2008-12-190934v1 114/19/4197    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 CrossRef Google Scholar Articles by Bandi, S. R. Articles by Sargin, B. PubMed PubMed Citation Articles by Bandi, S. R. Articles by Sargin, B. Related Collections Myeloid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA E3 ligase–defective Cbl mutants lead to a generalized mastocytosis and myeloproliferative disease Srinivasa Rao Bandi1,2,*, Christian Brandts1,2,*, Marion Rensinghoff1, Rebekka Grundler3, Lara Tickenbrock1,4, Gabriele Köhler5, Justus Duyster3, Wolfgang E. Berdel1, Carsten Müller-Tidow1, Hubert Serve1,2, on behalf of the Study Alliance Leukemias, and Bülent Sargin1 1 Department of Medicine, Hematology and Oncology and the Interdisciplinary Center for Clinical Research, University Hospital Muenster, Muenster; 2 Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt am Main; 3 Department of Internal Medicine III, Klinikum Rechts der Isar, Technical University of Munich, Munich; 4 University of Applied Science, Hochschule Hamm-Lippstadt, Hamm; and 5 Gerhard Domagk Institute of Pathology, University of Münster, Münster, Germany Somatic mutations of Kit have been found in leukemias and gastrointestinal stromal tumors. The proto-oncogene c-Cbl negatively regulates Kit and Flt3 by its E3 ligase activity and acts as a scaffold. We recently identified the first c-Cbl mutation in human disease in an acute myeloid leukemia patient, called Cbl-R420Q. Here we analyzed the role of Cbl mutants on Kit-mediated transformation. Coexpression of Cbl-R420Q or Cbl-70Z with Kit induced cytokine-independent proliferation, survival, and clonogenic growth. Primary murine bone marrow retrovirally transduced with c-Cbl mutants and transplanted into mice led to a generalized mastocytosis, a myeloproliferative disease, and myeloid leukemia. Overexpression of these Cbl mutants inhibited stem cell factor (SCF)–induced ubiquitination and internalization of Kit. Both Cbl mutants enhanced the basal activation of Akt and prolonged the ligand-dependent activation. Importantly, transformation was observed also with kinase-dead forms of Kit and Flt3 in the presence of Cbl-70Z, but not in the absence of Kit or Flt3, suggesting a mechanism dependent on receptor tyrosine kinases, but independent of their kinase activity. Instead, transformation depends on the Src family kinase Fyn, as c-Cbl coimmunoprecipitated with Fyn and inhibition abolished transformation. These findings may explain primary resistance to tyrosine kinase inhibitors targeted at receptor tyrosine kinases. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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