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Gain-of-function of mutated C-CBL tumour suppressor in 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, but also with gain-of-function mutations of proto-oncogenes. 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. 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 sensitivities to a broader spectrum of cytokines, including stem-cell factor (SCF, also known as KITLG), thrombopoietin (TPO, also known as THPO), IL3 and FLT3 ligand (FLT3LG), indicating the presence of a gain-of-function that could not be attributed to a simple loss-of-function. The gain-of-function effects of C-CBL mutants on cytokine sensitivity of HSPCs largely disappeared in a c-Cbl(+/+) background or by co-transduction of wild-type C-CBL, which suggests the pathogenic importance of loss of wild-type C-CBL alleles found in most cases of C-CBL-mutated myeloid neoplasms. Our findings provide a new insight into a role of gain-of-function mutations of a tumour suppressor associated with aUPD in the pathogenesis of some myeloid cancer subsets.

Pubmed ID: 19620960


  • Sanada M
  • Suzuki T
  • Shih LY
  • Otsu M
  • Kato M
  • Yamazaki S
  • Tamura A
  • Honda H
  • Sakata-Yanagimoto M
  • Kumano K
  • Oda H
  • Yamagata T
  • Takita J
  • Gotoh N
  • Nakazaki K
  • Kawamata N
  • Onodera M
  • Nobuyoshi M
  • Hayashi Y
  • Harada H
  • Kurokawa M
  • Chiba S
  • Mori H
  • Ozawa K
  • Omine M
  • Hirai H
  • Nakauchi H
  • Koeffler HP
  • Ogawa S



Publication Data

August 13, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: 2R01CA026038-30

Mesh Terms

  • Allelic Imbalance
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Chromosomes, Human, Pair 11
  • Female
  • Genes, Tumor Suppressor
  • Humans
  • Leukemia, Myeloid
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Nude
  • Models, Molecular
  • Molecular Sequence Data
  • Mutant Proteins
  • Mutation
  • NIH 3T3 Cells
  • Neoplasm Transplantation
  • Oncogenes
  • Phosphorylation
  • Protein Conformation
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitination
  • Uniparental Disomy
  • ras Proteins