文章：

Notch 1激活在T细胞急性淋巴细胞白血病的分子发病机制中的作用

Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia

原文发布日期：2006-04-13

DOI: 10.1038/nrc1880

类型: Review Article

开放获取: 否

要点：

1. T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive blood cancer that affects about 1,500 people per year in the United States. Significant advances have been made in the development of effective therapies for this otherwise rapidly fatal disease, which is most common in children and adolescents.
2. T-ALL can be classified into at least five different subtypes based on the activation of specific T-ALL oncogenes and associated gene-expression profiles that correlate with the stage of arrest in T-cell development.
3. The NOTCH1 gene is expressed in haematopoietic stem cells (HSCs) and controls several steps in thymocyte specification and differentiation. Chromosomal alterations that juxtapose a truncated, activated form of Notch1 (TAN1) with the T-cell receptor-β (TCRB) locus occur in less than 1% of all T-ALL cases.
4. Somatic activating mutations of Notch1 have been identified in more than 50% of all T-ALL cases and are found in all previously defined T-ALL subtypes. One set of mutations destabilizes the Notch heterodimerization domain, probably facilitating ligand-independent pathway activation, whereas mutations that disrupt the intracellular PEST (polypeptide enriched in proline, glutamate, serine and threonine) domain might function by increasing the half-life of transcriptionally active intracellular Notch 1 (ICN1).
5. The high prevalence of Notch1 mutations in T-ALL, and the dependence of T-ALL cases on Notch-1-pathway activation for unrestricted proliferation render this protein an excellent candidate for pharmacological intervention with γ-secretase inhibitors.
6. Studies of Notch 1 in the induction of T-ALL, using murine and zebrafish T-ALL models, might lead to the discovery of pharmacological inhibitors that specifically target other components in the Notch 1 pathway.
7. Emerging knowledge of the specific gene-expression profiles associated with T-ALL subtypes, the important function of Notch 1 in T-cell leukaemogenesis, and the development of novel, specific inhibitors should stimulate the development of disease-specific treatments that increase survival rates and improve the quality of life of patients with T-ALL.

要点翻译：

1. T细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性血液癌症，美国每年约有1500人患病。这种最常见于儿童和青少年的疾病原本进展迅速且致命，但在有效疗法研发方面已取得重大进展。
2. 根据特定T-ALL致癌基因的激活状态及与之相关的基因表达谱，T-ALL可分为至少五种亚型，这些特征与T细胞发育阻滞阶段相关。
3. NOTCH1基因在造血干细胞中表达，控制胸腺细胞定向分化的多个步骤。在不到1%的T-ALL病例中，会出现染色体变异导致截短型活化Notch1蛋白与T细胞受体β基因座并列的情况。
4. 超过50%的T-ALL病例存在Notch1体细胞激活突变，且该突变存在于所有已知T-ALL亚型。一类突变会破坏Notch异二聚化结构域稳定性，可能促进不依赖配体的通路激活；而破坏细胞内PEST结构域的突变则可能通过延长转录活性型胞内Notch1蛋白的半衰期发挥作用。
5. Notch1突变在T-ALL中的高发生率，以及T-ALL病例依赖Notch1通路激活实现无限增殖的特性，使得该蛋白成为γ-分泌酶抑制剂药物干预的理想靶点。
6. 通过小鼠和斑马鱼T-ALL模型对Notch1诱导T-ALL机制的研究，可能推动针对Notch1通路其他组分的特异性药理抑制剂的发现。
7. 对T-ALL亚型特异性基因表达谱的新认知、Notch1在T细胞白血病发生中的重要作用，以及新型特异性抑制剂的研发，将共同促进针对疾病特性的治疗方案发展，从而提高患者生存率并改善其生活质量。

英文摘要：

The chromosomal translocation t(7;9) in human T-cell acute lymphoblastic leukaemia (T-ALL) results in deregulated expression of a truncated, activated form of Notch 1 (TAN1) under the control of the T-cell receptor-β (TCRB) locus. Although TAN1 efficiently induces T-ALL in mouse models, t(7;9) is present in less than 1% of human T-ALL cases. The recent discovery of novel activating mutations in NOTCH1 in more than 50% of human T-ALL samples has made it clear that Notch 1 is far more important in human T-ALL pathogenesis than previously suspected.

摘要翻译： 

人类T细胞急性淋巴细胞白血病（T-ALL）中的染色体易位t(7;9)导致一种截短且激活形式的Notch1（TAN1）在T细胞受体β（TCRB）基因座调控下异常表达。尽管TAN1在小鼠模型中能有效诱发T-ALL，t(7;9)在人类T-ALL病例中却不足1%。近期研究发现，超过50%的人类T-ALL样本中存在NOTCH1的新型激活突变，表明Notch1在人类T-ALL发病机制中的作用远比以往认为的更为重要。

原文链接：

Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia