Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms
Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms
复制标题
DOI：
10.1038/nature08240
复制
发表时间：
2009-08-13
期刊：
影响因子：
64.8
通讯作者：
Ogawa, Seishi
中科院分区：
文献类型：
--
作者：
Sanada, Masashi;Suzuki, Takahiro;Ogawa, Seishi
获得性单倍体（aUPD）是癌症基因组的共同特征，导致杂合性丧失。aUPD不仅与肿瘤抑制基因的功能丧失突变有关(1)，也与原癌基因的功能获得突变有关(2)。在这里，我们展示了独特的C-CBL（也称为CBL）肿瘤抑制因子的功能获得突变，该突变与11q臂的髓系肿瘤的aUPD密切相关，表现出骨髓增生性特征。C-CBL原癌基因是v-Cbl的细胞同源物，编码E3泛素连接酶并负性调节酪氨酸激酶的信号转导（3-6）。在大多数11q- aupd阳性的髓系恶性肿瘤中发现纯合子C-CBL突变。尽管C-CBL突变在NIH3T3细胞中具有致癌作用，但C-CBL在功能和基因上都具有肿瘤抑制作用。C-CBL突变体不具有E3泛素连接酶活性，但抑制野生型C-CBL和CBL-B（也称为CBLB）的活性，导致细胞因子刺激后酪氨酸激酶的激活时间延长。与c-Cbl(+/+) HSPCs相比，c-Cbl（-/-）造血干细胞/祖细胞（HSPCs）对多种细胞因子的敏感性增强，c-Cbl突变体转导成c-Cbl(-/-) HSPCs进一步增强了它们对更广泛细胞因子的敏感性，包括干细胞因子（SCF，也称为KITLG）、血小板生成素（TPO，也称为THPO）、IL3和FLT3配体（FLT3LG）。表明存在功能的获得，而不能归因于简单的功能丧失。C-CBL突变体对HSPCs细胞因子敏感性的功能获得效应在C-CBL（-/-）背景下或通过野生型C-CBL的共转导基本消失，这表明在大多数C-CBL突变的髓系肿瘤中发现的野生型C-CBL等位基因缺失具有重要的致病作用。我们的研究结果为与aUPD相关的肿瘤抑制因子的功能获得突变在一些髓系癌亚群的发病机制中的作用提供了新的见解。
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(3-6). 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 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.