文章：

慢性髓性白血病作为人类癌症疾病进化的模型

Chronic myeloid leukaemia as a model of disease evolution in human cancer

原文发布日期：2007-06-01

DOI: 10.1038/nrc2147

类型: Review Article

开放获取: 否

要点：

1. Chronic myeloid leukaemia (CML) can be considered, for some aspects, a model for malignant tumours that evolve through a multi-step pathogenetic process. In its natural history, CML is usually diagnosed in chronic phase (CP) and then progresses through an accelerated phase to a nearly invariably fatal blast crisis (BC).
2. The mechanisms of transformation to BC are varied and not entirely understood. So far the best characterized include differentiation arrest, genomic instability, telomere shortening and loss of tumour-suppressor functions.
3. The differentiation arrest of the transformed BC clone is caused by the suppression of translation of the transcription factor CEBPα induced by the BCR-ABL oncoprotein in CML cells, through increased stability of the heterogenous nuclear ribonucleoprotein E2 translational regulator.
4. The increased genomic instability in CML cells is the result of their reduced capacity to survey the genome for DNA damage and to correctly repair DNA lesions, which leads to the accumulation of deleterious mutations in genes that are essential for maintaining normal cell physiology and maturation.
5. The impairment of several tumour-suppressor genes has been variably associated with BC of CML, including TP53, retinoblastoma 1, CDKN2A and others. Protein phosphatase 2a (PP2A) has an important role, as it is inhibited by BCR-ABL in BC cells by the post-transcriptional upregulation of SET, a phosphoprotein that is frequently overexpressed in other leukaemias and solid tumours.
6. Recent expression profiling of cells from different stages of CML has uncovered several genes that are differentially expressed in BC and in extremely aggressive forms of the disease. These are likely to be associated with the kinetics of blastic transformation.
7. It is envisaged that the identification of the most pathologically relevant genetic lesions for the development of BC will allow the early diagnosis of impending disease progression and the design of new treatment strategies to halt this process. Such an approach can become the paradigm for therapy decision making in other types of cancer.

要点翻译：

1. 慢性粒细胞白血病（CML）在某些方面可被视为通过多步骤发病机制演变的恶性肿瘤模型。在其自然病程中，CML通常在慢性期（CP）被诊断，随后经加速期进展至几乎必然致命的急变期（BC）。  
2. 向急变期转化的机制多样且尚未完全阐明。目前最明确的机制包括分化阻滞、基因组不稳定性、端粒缩短及肿瘤抑制功能丧失。  
3. 经转化的急变期克隆的分化阻滞是由BCR-ABL癌蛋白通过增强异质核核糖核蛋白E2翻译调节因子的稳定性，抑制CML细胞中转录因子CEBPα的翻译所引起。  
4. CML细胞基因组不稳定性增加源于其监测DNA损伤及正确修复DNA缺陷的能力下降，这导致维持正常细胞生理功能和成熟所必需基因中有害突变的积累。  
5. 多种肿瘤抑制基因的损伤与CML急变期存在不同程度关联，包括TP53、视网膜母细胞瘤蛋白1、CDKN2A等。蛋白磷酸酶2A（PP2A）具有重要作用，其在急变期细胞中被BCR-ABL通过转录后上调SET（一种常在其他白血病和实体瘤中过表达的磷蛋白）所抑制。  
6. 近期对不同阶段CML细胞的表达谱分析发现，在急变期和极具侵袭性的疾病形式中存在多个差异表达基因。这些基因很可能与急骤转化的动力学相关。  
7. 学界预期，明确与急变期发展最相关的病理性基因损伤将有助于实现疾病进展的早期诊断，并设计新的治疗策略以阻断该进程。这种方法可能成为其他癌症治疗决策制定的范式。

英文摘要：

Chronic myeloid leukaemia (CML) can be considered as a paradigm for neoplasias that evolve through a multi-step process. CML is also one of the best examples of a disease that can be targeted by molecular therapy; however, the success of new 'designer drugs' is largely restricted to the chronic phase of the disease. If not cured at this stage, CML invariably progresses and transforms into an acute-type leukaemia undergoing a 'blast crisis'. The causes of this transformation are still poorly understood. What mechanisms underlie this progression, and are they shared by other common cancers?

摘要翻译： 

慢性粒细胞白血病（CML）可被视为通过多步骤过程演变的肿瘤范例。CML也是分子靶向治疗最成功的疾病范例之一；然而，新型"设计药物"的疗效主要限于疾病慢性期。若在此阶段未能治愈，CML将不可避免地进展并转化为急性白血病，即发生"原始细胞危象"。这种转化的机制尚未阐明。其进展机制是什么？是否与其他常见癌症存在共性？

原文链接：

Chronic myeloid leukaemia as a model of disease evolution in human cancer