Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms

Gain-of-function oncogenes Normal human cells contain a complete set of chromosomes from each parent, but in some cancers both copies of parts of particular chromosomes are from the same parent — a phenomenon known as acquired uniparental disomy. Work on genomic DNA from over 200 bone marrow samples from patients with myeloid neoplasms has uncovered a high incidence of inheritance of two copies of part of chromosome 11 from a single parent, containing a gain-of-function mutation of the tumour suppressor C-CBL that causes fibroblast cells to become cancerous and renders haematopoietic cells more sensitive to cytokine stimulation. The data support the idea that c-Cbl is both a growth-suppressing tumour suppressor gene and, when mutated, a growth-promoting oncogene, a situation similar to that found for the p53 tumour suppressor. Acquired uniparental disomy (aUPD), a common feature of cancer genomes, is associated with gain-of-function mutations of proto-oncogenes as well as with loss-of-function mutations of tumour suppressor genes. Here, gain-of-function mutations of the C-CBL tumour suppressor are shown to be tightly associated with aUPD of the 11q arm in certain myeloid neoplasms. Acquired uniparental disomy (aUPD) is a common feature of cancer genomes, leading to loss of heterozygosity. aUPD is associated not only with loss-of-function mutations of tumour suppressor genes 1 , but also with gain-of-function mutations of proto-oncogenes 2 . Here we show unique gain-of-function mutations of the C-CBL (also known as CBL) tumour suppressor that are tightly associated with aUPD of the 11q arm in myeloid neoplasms showing myeloproliferative features. The C-CBL proto-oncogene, a cellular homologue of v-Cbl , encodes an E3 ubiquitin ligase and negatively regulates signal transduction of tyrosine kinases 3 , 4 , 5 , 6 . Homozygous C-CBL mutations were found in most 11q-aUPD-positive myeloid malignancies. Although the C-CBL mutations were oncogenic in NIH3T3 cells, c-Cbl was shown to functionally and genetically act as a tumour suppressor. C-CBL mutants did not have E3 ubiquitin ligase activity, but inhibited that of wild-type C-CBL and CBL-B (also known as CBLB), leading to prolonged activation of tyrosine kinases after cytokine stimulation. c-Cbl -/- haematopoietic stem/progenitor cells (HSPCs) showed enhanced sensitivity to a variety of cytokines compared to c-Cbl +/+ HSPCs, and transduction of C-CBL mutants into c-Cbl -/- HSPCs further augmented their sensitivi