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Blood, 1 August 2007, Vol. 110, No. 3, pp. 1004-1012.
Prepublished online as a Blood First Edition Paper on May 14, 2007; DOI 10.1182/blood-2007-01-066076.
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NEOPLASIA
Flt3-dependent transformation by inactivating c-Cbl mutations in AML
Bülent Sargin1,
Chunaram Choudhary1,
Nicola Crosetto2,
Mirko H. H. Schmidt2,
Rebekka Grundler3,
Marion Rensinghoff1,
Christine Thiessen1,
Lara Tickenbrock1,
Joachim Schwäble1,
Christian Brandts1,
Benjamin August1,
Steffen Koschmieder1,
Srinivasa Rao Bandi1,
Justus Duyster3,
Wolfgang E. Berdel1,
Carsten Müller-Tidow1,
Ivan Dikic2, and
Hubert Serve1
1 Department of Medicine, Hematology and Oncology and the Interdisciplinary Center for Clinical Research, University Hospital Münster, Münster;
2 Institute of Biochemistry II, Goethe University Medical School, Frankfurt;
3 Department of Internal Medicine III, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
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. Coexpression 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.
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