E3 ligase-defective Cbl mutants lead to a generalized mastocytosis and myeloproliferative disease
| Autor: | Srinivasa Rao, Bandi, Christian, Brandts, Marion, Rensinghoff, Rebekka, Grundler, Lara, Tickenbrock, Gabriele, Köhler, Justus, Duyster, Wolfgang E, Berdel, Carsten, Müller-Tidow, Hubert, Serve, Bülent, Sargin, Martin, Wolf |
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| Rok vydání: | 2009 |
| Předmět: |
Immunology
Biology Ligands environment and public health Biochemistry Proto-Oncogene Mas Receptor tyrosine kinase Mice FYN hemic and lymphatic diseases Chlorocebus aethiops Animals Humans Src family kinase Proto-Oncogene Proteins c-cbl Kinase activity Protein kinase B Bone Marrow Transplantation Mice Inbred BALB C Myeloproliferative Disorders fungi Ubiquitination Myeloid leukemia Cell Biology Hematology enzymes and coenzymes (carbohydrates) Disease Models Animal Proto-Oncogene Proteins c-kit Cell Transformation Neoplastic COS Cells Mutation Cancer research biology.protein Mutagenesis Site-Directed Female biological phenomena cell phenomena and immunity Signal transduction Tyrosine kinase Mastocytosis Signal Transduction |
| Zdroj: | Blood. 114(19) |
| ISSN: | 1528-0020 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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