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

Masashi Sanada, Takahiro Suzuki, Lee Yung Shih*, Makoto Otsu, Motohiro Kato, Satoshi Yamazaki, Azusa Tamura, Hiroaki Honda, Mamiko Sakata-Yanagimoto, Keiki Kumano, Hideaki Oda, Tetsuya Yamagata, Junko Takita, Noriko Gotoh, Kumi Nakazaki, Norihiko Kawamata, Masafumi Onodera, Masaharu Nobuyoshi, Yasuhide Hayashi, Hiroshi HaradaMineo Kurokawa, Shigeru Chiba, Hiraku Mori, Keiya Ozawa, Mitsuhiro Omine, Hisamaru Hirai, Hiromitsu Nakauchi, H. Phillip Koeffler, Seishi Ogawa

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

344 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)904-908
Number of pages5
JournalNature
Volume460
Issue number7257
DOIs
StatePublished - 13 08 2009

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