文章：

唐氏综合症儿童白血病的起源

Origins of leukaemia in children with Down syndrome

原文发布日期：2005-01-01

DOI: 10.1038/nrc1525

类型: Review Article

开放获取: 否

要点：

1. Children with Down syndrome (DS, characterized by constitutional trisomy 21) have a 10–20-fold increased incidence of acute leukaemia. Acute megakaryoblastic leukaemia (AMKL) is particularly prevalent, with an estimated 500-fold increased relative risk compared with the general population.
2. Acute myeloid leukaemia in children with DS occurs at a younger age, is usually AMKL and frequently preceded by a phase of abnormal haematopoietic differentiation (myelodysplastic syndrome) and shows increased sensitivity to chemotherapy.
3. A transient form of megakaryoblastic leukaemia — known as transient leukaemia (TL) — is found in 10% of newborn infants with DS and in most cases resolves spontaneously. However, an estimated 20% of children with DS who recover from TL subsequently develop AMKL within the first 4 years of life.
4. The leukaemic blasts of DS-AMKL harbour somatic mutations of GATA1, which encodes a haematopoietic transcription factor encoded on the X chromosome. Most mutations cluster within exon 2 and result in the expression of a truncated mutant protein, GATA1s, that lacks the amino-terminal transcriptional activation domain.
5. GATA1 mutations are also present in TL blasts detected at birth, indicating that they represent an early event occurring in utero. Concordant GATA1 mutations and cytogenetic abnormalities in TL and DS-AMKL blasts of the same individual support a model in which DS-AMKL arises from a persistent subclone of TL cells as the result of additional, as yet undetermined, mutations.
6. Megakaryoblastic leukaemia that develops on the basis of trisomy 21 and somatic GATA1 mutations is a unique biological model of the incremental process of leukaemic transformation.

要点翻译：

1. 唐氏综合征（DS，特征为先天性21三体）患儿急性白血病发病率增高10-20倍。急性巨核细胞白血病（AMKL）尤其高发，估计相对风险较普通人群增加500倍。
2. DS患儿急性髓系白血病发病年龄更小，通常为AMKL，且常先出现造血分化异常阶段（骨髓增生异常综合征），对化疗敏感性增强。
3. 10%的DS新生儿会出现一种短暂性巨核细胞白血病——称为一过性白血病（TL），多数病例可自行缓解。但约20%从TL恢复的DS患儿会在4岁前发展为AMKL。
4. DS-AMKL的白血病原始细胞携带GATA1基因体细胞突变，该基因编码X染色体上的造血转录因子。大多数突变聚集于外显子2，导致表达缺失氨基端转录激活结构域的截短突变蛋白GATA1s。
5. 出生时检测到的TL原始细胞也存在GATA1突变，表明这是宫内发生的早期事件。同一患者TL与DS-AMKL原始细胞中一致的GATA1突变和细胞遗传学异常，支持DS-AMKL源于TL细胞持久亚克隆经由额外未知突变演进的发病模型。
6. 基于21三体和体细胞GATA1突变发展的巨核细胞白血病，为白血病转化渐进过程提供了独特的生物学模型。

英文摘要：

Transient megakaryoblastic leukaemia is found in 10% of newborns with Down syndrome, characterized by constitutional trisomy 21. Although in most cases the leukaemic cells disappear spontaneously after the first months of life, irreversible acute megakaryoblastic leukaemia develops in 20% of these individuals within 4 years. The leukaemic cells typically harbour somatic mutations of the gene encoding GATA1, an essential transcriptional regulator of normal megakaryocytic differentiation. Leukaemia that specifically arises in the context of constitutional trisomy 21 and somatic GATA1 mutations is a unique biological model of the incremental process of leukaemic transformation.

摘要翻译： 

10%的唐氏综合征新生儿会出现一过性巨核细胞白血病，其特征为21三体综合征。尽管大多数情况下白血病细胞在出生后数月内自发消失，但其中20%的个体在4年内会发展为不可逆的急性巨核细胞白血病。白血病细胞通常携带GATA1基因的体细胞突变，而GATA1是正常巨核细胞分化的关键转录调控因子。由21三体综合征和GATA1体细胞突变共同导致的白血病，是白血病转化渐进过程的一个独特生物学模型。

原文链接：

Origins of leukaemia in children with Down syndrome