E3 ligase-defective Cbl mutants lead to a generalized mastocytosis and myeloproliferative disease.

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.
Mesh Terms:
Animals, Bone Marrow Transplantation, COS Cells, Cell Transformation, Neoplastic, Cercopithecus aethiops, Disease Models, Animal, Female, Humans, Ligands, Mastocytosis, Mice, Mice, Inbred BALB C, Mutagenesis, Site-Directed, Mutation, Myeloproliferative Disorders, Proto-Oncogene Proteins c-cbl, Proto-Oncogene Proteins c-kit, Signal Transduction, Ubiquitination
Blood
Date: Nov. 05, 2009
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