The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling
The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling
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DOI：
10.1158/0008-5472.can-06-4381
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发表时间：
2007-06-15
期刊：
影响因子：
11.2
通讯作者：
Sangfelt, Olle
中科院分区：
文献类型：
--
作者：
Malyukova, Alena;Dohda, Takeaki;Sangfelt, Olle
Notch信号在正常t细胞发育中起着至关重要的作用，Notch I在t细胞急性淋巴细胞白血病（T-ALL）中经常发生突变，导致Notch信号异常高。在本报告中，我们确定T-ALL突变是否不仅发生在Notch1中，也发生在Notch1的负调节因子F-box蛋白hCdc4 （Sel-10， Ago或Fbxw7）中。我们发现hCDC4基因在超过30%的儿童T-ALL患者及其衍生细胞系的白血病细胞中发生突变。发现的大多数hCDC4突变是位于hCDC4底物结合区的关键精氨酸残基（Arg465、AX9479和Arg 505）的错义替换。对hCdc4失活的细胞和含有hCdc4突变的T-ALL细胞表现出Notchi蛋白半衰期增加，这与hCdc4在泛素依赖性Notchl蛋白水解中的作用一致。此外，在HCT 116 hCdc4阴性细胞中恢复野生型而非突变型hCdc4导致Notchl泛素化增加和Notchl信号传导减少。这些结果表明，hCdc4突变会干扰体内正常的Notchl调节。最后，我们发现hCDC4和NOTCH突变可以发生在相同的癌症中，携带hCDC4和/或NOTCH突变的患者具有良好的总生存期。总之，这些数据表明hCDC4突变在T-ALL中是一个常见的事件，并提示hCDC4突变和NOTCH-1的功能获得性突变可能协同促进儿童T-ALL白血病发生的发展。
Notch signaling is of crucial importance in normal T-cell development and Notch I is frequently mutated in T-cell acute lymphoblastic leukemias (T-ALL), leading to aberrantly high Notch signaling. In this report, we determine whether T-ALL mutations occur not only in Notch1 but also in the F-box protein hCdc4 (Sel-10, Ago, or Fbxw7), a negative regulator of Notch1. We show that the hCDC4 gene is mutated in leukemic cells from more than 30% of patients with pediatric T-ALL and derived cell lines. Most hCDC4 mutations found were missense substitutions at critical arginine residues (Arg465, AX9479, and Arg 505) localized in the substrate-binding region of hCdc4. Cells inactivated for hCdc4 and T-ALL cells containing hCDC4 mutations exhibited an increased Notchi protein half-life, consistent with the proposed role of hCdc4 in ubiquitin-dependent proteolysis of Notchl. Furthermore, restoration of wild-type but not mutant hCdc4 in HCT 116 hCDC4-negative cells led to an increased Notchl ubiquitylation and decreased Notchl signaling. These results show that hCdc4 mutations interfere with normal Notchl regulation in vivo. Finally, we found that mutations in hCDC4 and NOTCH] can occur in the same cancers and that patients carrying hCDC4 and/or NOTCH] mutations have a favorable overall survival. Collectively, these data show that mutation of hCDC4 is a frequent event in T-ALL and suggest that hCDC4 mutations and gainof-function mutations in NOTCH-1 might synergize in contributing to the development of pediatric T-ALL leukemogenesis.