文章：

儿童急性淋巴细胞白血病的病因机制

A causal mechanism for childhood acute lymphoblastic leukaemia

原文发布日期：2018-05-21

DOI: 10.1038/s41568-018-0015-6

类型: Review Article

开放获取: 否

英文摘要：

In this Review, I present evidence supporting a multifactorial causation of childhood acute lymphoblastic leukaemia (ALL), a major subtype of paediatric cancer. ALL evolves in two discrete steps. First, in utero initiation by fusion gene formation or hyperdiploidy generates a covert, pre-leukaemic clone. Second, in a small fraction of these cases, the postnatal acquisition of secondary genetic changes (primarily V(D)J recombination-activating protein (RAG) and activation-induced cytidine deaminase (AID)-driven copy number alterations in the case of ETS translocation variant 6 (ETV6)–runt-related transcription factor 1 (RUNX1)+ ALL) drives conversion to overt leukaemia. Epidemiological and modelling studies endorse a dual role for common infections. Microbial exposures earlier in life are protective but, in their absence, later infections trigger the critical secondary mutations. Risk is further modified by inherited genetics, chance and, probably, diet. Childhood ALL can be viewed as a paradoxical consequence of progress in modern societies, where behavioural changes have restrained early microbial exposure. This engenders an evolutionary mismatch between historical adaptations of the immune system and contemporary lifestyles. Childhood ALL may be a preventable cancer.

摘要翻译： 

在本综述中，我提出了支持儿童急性淋巴细胞白血病（ALL）——这一儿科癌症主要亚型——多因素致病机制的证据。ALL的形成分为两个独立步骤：首先，在子宫内由融合基因形成或超二倍体启动，产生隐蔽的白血病前克隆；其次，部分病例在出生后获得继发性遗传改变（以ETV6-RUNX1阳性ALL为例，主要由RAG蛋白和活化诱导胞苷脱氨酶驱动的拷贝数变异引发），推动其向显性白血病转化。流行病学与模型研究证实常见感染具有双重作用：生命早期接触微生物具有保护效应，但若缺乏此类接触，后期感染则会触发关键的继发性突变。遗传因素、随机事件及饮食可能进一步修饰患病风险。儿童ALL可视为现代社会进步的悖论性后果——行为模式改变限制了早期微生物接触，导致免疫系统的历史适应与当代生活方式之间产生进化失配。儿童ALL或许是一种可预防的癌症。

原文链接：

A causal mechanism for childhood acute lymphoblastic leukaemia