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Flt3-dependent transformation by inactivating c-Cbl mutations in AML

2007; Elsevier BV; Volume: 110; Issue: 3 Linguagem: Inglês

10.1182/blood-2007-01-066076

1528-0020

Bülent Sargin, Chunaram Choudhary, Nicola Crosetto, Mirko H. H. Schmidt, Rebekka Grundler, Marion Rensinghoff, Christine Thiessen, Lara Tickenbrock, Joachim Schwäble, Christian Brandts, Benjamin K. August, Steffen Koschmieder, Srinivasa Rao Bandi, Justus Duyster, Wolfgang E. Berdel, Carsten Müller‐Tidow, Ivan Đikić, Hubert Serve,

Histone Deacetylase Inhibitors Research

Abstract 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.