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Flt3-dependent transformation by inactivating c-Cbl mutations in AML.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Sargin, Bülent Choudhary, Chunaram Crosetto, Nicola Schmidt, Mirko H. H. Grundler, Rebekka Rensinghoff, Marion Thiessen, Christine Tickenbrock, Lara Schwäble, Joachim Brandts, Christian August, Benjamin Glass Koschmieder, Steffen Srinivasa Rao Bandi Duyster, Justus Berdel, Wolfgang E. Müller-Tidow, Carsten Dikic, Ivan Serve, Hubert |
| Copyright Year | 2007 |
| 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. |
| Starting Page | 293 |
| Ending Page | 293 |
| Page Count | 1 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.bloodjournal.org/content/bloodjournal/early/2007/04/19/blood-2007-01-066076.full.pdf?sso-checked=true |
| PubMed reference number | 17446348v1 |
| Volume Number | 110 |
| Issue Number | 3 |
| Journal | Blood |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Bone Marrow CBL gene Leukemia, Myelocytic, Acute Myeloid Leukemia Oncogenes Point Mutation Protein Tyrosine Kinase Proto-Oncogene Proteins c-cbl Proto-Oncogenes Receptor Protein-Tyrosine Kinases Signal Transduction Ubiquitination cytokine erbB-2 Receptor ubiquitin-protein ligase activity |
| Content Type | Text |
| Resource Type | Article |
