文章：

骨髓增生异常综合征表型异质性的遗传基础

The genetic basis of phenotypic heterogeneity in myelodysplastic syndromes

原文发布日期：2012-11-23

DOI: 10.1038/nrc3321

类型: Review Article

开放获取: 否

要点：

1. Myelodysplastic syndromes (MDS) are a group of diseases that present with the paradox of cytopenia despite a cellular bone marrow. This can be explained by excessive cytokine-mediated intramedullary apoptosis of haematopoietic cells.
2. Emerging biological insights are providing a molecular basis for the phenotypic and clinical heterogeneity of MDS.
3. Defects in ribosomal biogenesis have been associated with both congenital and acquired anaemias. These defects lead to a ribosomal stress response in the cell with an increase in p53 expression, thus providing one molecular explanation for the excessive apoptosis of MDS cells.
4. Abnormal regulation of haematopoiesis by microRNAs (miRNAs) has now been shown to contribute to the pathology of MDS.
5. The importance of epigenetic changes in MDS — initially suspected because of the responsiveness of patients with MDS to demethylating agents — has been molecularly demonstrated through the identification of mutations in genes controlling chromatin methylation and deacetylation.
6. Multiple oncogenes and tumour suppressor genes are mutated, although none has been specifically associated with MDS.
7. Mutations of specific spliceosome genes, either alone or combined with other genetic abnormalities, may be responsible for different MDS phenotypes.
8. An incremental understanding of molecular lesions accounting for clonal expansion in the presence of excessive apoptosis — which is the paradox in MDS — will be the roadmap to improved and targeted therapies.

要点翻译：

1. 骨髓增生异常综合征（MDS）是一组表现为骨髓细胞丰富却存在血细胞减少这一矛盾现象的疾病。这可通过造血细胞因过度细胞因子介导的髓内凋亡来解释。
2. 新兴的生物学见解正在为MDS的表型和临床异质性提供分子基础。
3. 核糖体生物合成缺陷与先天性和获得性贫血均存在关联。这些缺陷会引发细胞内的核糖体应激反应，导致p53表达增加，从而为MDS细胞的过度凋亡提供了分子层面的解释。
4. microRNA（miRNA）对造血作用的异常调控现已被证实参与MDS的病理过程。
5. 表观遗传改变在MDS中的重要性——最初因MDS患者对去甲基化药物的治疗反应而被推测——通过控制染色质甲基化和去乙酰化基因突变的鉴定，已在分子层面得到证实。
6. 多种癌基因和抑癌基因存在突变，但尚未发现特异性与MDS相关的突变。
7. 特定剪接体基因的突变，无论是单独发生还是与其他遗传异常结合，都可能导致不同的MDS表型。
8. 对在过度凋亡（即MDS的矛盾现象）背景下驱动克隆扩增的分子病变的逐步深入理解，将成为改进靶向治疗路线图。

英文摘要：

Myelodysplastic syndromes (MDS) are malignant clonal disorders of haematopoietic stem cells and their microenvironment, affecting older individuals (median age ∼70 years). Unique features that are associated with MDS — but which are not necessarily present in every patient with MDS — include excessive apoptosis in maturing clonal cells, a pro-inflammatory bone marrow microenvironment, specific chromosomal abnormalities, abnormal ribosomal protein biogenesis, the presence of uniparental disomy, and mutations affecting genes involved in proliferation, methylation and epigenetic modifications. Although emerging insights establish an association between molecular abnormalities and the phenotypic heterogeneity of MDS, their origin and progression remain enigmatic.

摘要翻译： 

骨髓增生异常综合征（MDS）是造血干细胞及其微环境的恶性克隆性疾病，主要影响老年人（中位年龄约70岁）。MDS的独特特征包括：成熟克隆细胞过度凋亡、骨髓微环境呈促炎状态、特异性染色体异常、核糖体蛋白生物合成异常、单亲二倍体存在，以及影响增殖、甲基化和表观遗传修饰的基因突变——但这些特征并非在每个患者中都出现。尽管新进展揭示了分子异常与MDS表型异质性之间的关联，其起源和进展机制仍不清楚。

原文链接：

The genetic basis of phenotypic heterogeneity in myelodysplastic syndromes