title: Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms.
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.
authors.affiliation: Cancer Genomics Project, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Lee-Yung
authors.initials: LY
authors.lastname: Shih
authors.forename: Makoto
authors.initials: M
authors.lastname: Otsu
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Azusa
authors.initials: A
authors.lastname: Tamura
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Honda
authors.forename: Mamiko
authors.initials: M
authors.lastname: Sakata-Yanagimoto
authors.forename: Keiki
authors.initials: K
authors.lastname: Kumano
authors.forename: Hideaki
authors.initials: H
authors.lastname: Oda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamagata
authors.forename: Junko
authors.initials: J
authors.lastname: Takita
authors.forename: Noriko
authors.initials: N
authors.lastname: Gotoh
authors.forename: Kumi
authors.initials: K
authors.lastname: Nakazaki
authors.forename: Norihiko
authors.initials: N
authors.lastname: Kawamata
authors.forename: Masafumi
authors.initials: M
authors.lastname: Onodera
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nobuyoshi
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Harada
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
authors.forename: Shigeru
authors.initials: S
authors.lastname: Chiba
authors.forename: Hiraku
authors.initials: H
authors.lastname: Mori
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Omine
authors.forename: Hisamaru
authors.initials: H
authors.lastname: Hirai
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D022981:Allelic Imbalance; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D009857:Oncogenes / Q000235:genetics; D010766:Phosphorylation; D011487:Protein Conformation; D000090063:Proto-Oncogene Mas; D050721:Proto-Oncogene Proteins c-cbl / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D054875:Ubiquitination; D024182:Uniparental Disomy / Q000235:genetics; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C000715470:MAS1 protein, human; D050505:Mutant Proteins; D000090063:Proto-Oncogene Mas; D050721:Proto-Oncogene Proteins c-cbl; D018631:ras Proteins; C067419:CBL protein, human; C493849:Cbl protein, mouse